Egfr inhibitors

ABSTRACT

The present disclosure provides a compound represented by structural formula (I): or a pharmaceutically acceptable salt thereof useful for treating a cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional Application No.62/953,030, filed Dec. 23, 2019. The entire contents of theaforementioned application are incorporated herein by reference.

BACKGROUND

EGFR (Epidermal Growth Factor Receptor) is a member of the erbB receptorfamily, which includes transmembrane protein tyrosine kinase receptors.By binding to its ligand, such as epidermal growth factor (EGF), EGFRcan form a homodimer on the cell membrane or form a heterodimer withother receptors in the family, such as erbB2, erbB3, or erbB4. Theformation of these dimers can cause the phosphorylation of key tyrosineresidues in EGFR cells, thereby activating a number of downstreamsignaling pathways in cells. These intracellular signaling pathways playan important role in cell proliferation, survival and anti-apoptosis.Disorders of EGFR signal transduction pathways, including increasedexpression of ligands and receptors, EGFR gene amplification andalterations such as mutations, deletions and the like, can promotemalignant transformation of cells and play an important role in tumorcell proliferation, invasion, metastasis and angiogenesis. For example,alterations such as mutations and deletions in the EGFR gene are foundin non-small lung cancer (NSCLC) tumors. The two most frequent EGFRalternations found in NSCLC tumors are short in-frame deletions in exon19 (del19) and L858R, a single missense mutation in exon 21 (CancerDiscovery 2016 6(6) 601). These two alterations cause ligand-independentEGFR activation and are referred to as primary or activating mutationsin EGFR mutant NSCLC (EGFR M+). Clinical experience shows an objectiveresponse rate (ORR) of approximately 60-85% in EGFR M+NSCLC patientstreated first line (1L) with EGFR tyrosine kinase inhibitors (TKIs)erlotinib, gefitinib, afatinib and osimertinib (Lancet Oncol. 2010 Vol.11, 121; Lancet Oncol. 2016 Vol. 17, 577; N. Engl. J. Med. 2017 Nov. 18Doi:10.1056/NEJMoa1713137; Lancet Oncol. 2011 Vol. 12, 735), thusdemonstrating that EGFR mutant NSCLC tumors depend on oncogenic EGFRactivity for survival and proliferation and establishing del19 and L858Rmutated EGFR as oncogenic drivers of disease and thus, validating drugtargets and biomarkers for the treatment of NSCLC.

However, after an average of 10-12 months of treatment with firstgeneration (erlotinib and gefitinib) and second generation (afatinib)EGFR TKIs, resistance to these small molecule inhibitors has beenobserved in almost all NSCLC patients (Lancet Oncol. 2010 February;11(2):121-8; Lancet Oncol. 2016 May; 17(5):577-89; Lancet Oncol. 2011August; 12(8):735-42). The most prominent resistance mechanism to firstand second generation EGFR TKIs is due to the secondary mutation in EGFRof T790M, occurs in 50% to 70% of patients progressing on 1st and 2ndgeneration EGFR inhibitors. (Blakely, 2012; Kobayashi, 2005). Thissecondary mutation reduces the affinity of the drug with the target,thereby producing drug resistance, and resulting in tumor recurrence ordisease progression.

In view of the prevelance of this mutation in drug resistance producedin therapy targeting EGFR of lung cancer, a number of companies haveattempted to develop new small molecule EGFR inhibitors for treatingthese patients with drug-resistant lung cancer by inhibiting theresistant mutant EGFR-T790M. For example, osimertinib (Tagrisso®), athird generation EGFR TKI, has been developed to treat NSCLC patients ifthe cancer cells are positive for the primary EGFR mutations del19 orL858R with or without the T790M mutation in the gene coding for EGFR.

Although the third generation EGFR TKI, osimertinib, has shown efficacyon NSCLC patients, unfortunately, resistance mediated by an exon 20 C797mutation in EGFR usually develops within approximately 10 months(European Journal of Medicinal Chemistry 2017 Vol. 142: 32-47) andaccounts for the majority of osimertinib resistance cases (CancerLetters 2016 Vol. 385: 51-54). The EGFR del19/L858R T790M C797S cismutant kinase variant typically emerges in second line (2L) patientsfollowing treatment with osimertinib and is often referred to as “triplemutant” EGFR and it can no longer be inhibited by first, second, orthird generation EGFR inhibitors.

No approved EGFR TKI can inhibit the triple mutant variant. Therefore,there is a need to develop new EGFR inhibitors, which can inhibit withhigh selectivity EGFR mutants with the triple mutant, del19/L858R T790MC797S, while at the same time have no or low activity to wild-type EGFR.In addition to treating a mutant form of EGFR for which there is nocurrent therapy, such selective EGFR inhibitors are likely to be moresuitable as therapeutic agents, particularly for the treatment ofcancer, due to reduction of toxicologies (diarrhea, skin rash)associated with wild-type EGFR inhibition.

SUMMARY

The applicant has discovered novel compounds which are effectiveinhibitors of certain mutant forms of EGFR (see Synthetic Examples1-43). In particular, it has been demonstrated that the compounds of thepresent disclosure effectively inhibit certain mutant forms of EGFR.Compounds of the disclosure (also referred to herein as the “disclosedcompounds”) or pharmaceutically acceptable salts thereof effectivelyinhibit EGFR with one or more alterations, including L858R and/or exon19 deletion mutation, T790M mutation, and/or C797S mutation. Compoundsof the disclosure or pharmaceutically acceptable salts thereofeffectively inhibit EGFR with L858R and/or exon 19 deletion mutation,T790M mutation, and C797S mutation (hereinafter “EGFR with LRTMCSmutations” or “triple mutant EGFR”) (see Biological Example 1) and canbe used treat various cancers, for example, lung cancer (see BiologicalExample 2). Importantly, the disclosed compounds are selective EGFRinhibitors, i.e., the disclosed compounds have no or low activityagainst wild-type EGFR and the kinome. Advantages associated with suchselectivity may include facilitating efficacious dosing and reducingEGFR-mediated on-target toxicities. Some of the disclosed compoundsexhibit good penetration of the brain and blood brain barrier (e.g., aPGP efflux ratio of less than 5). As such, the compounds of thedisclosure or pharmaceutically acceptable salts thereof are expected tobe effective for the treatment of metastatic cancer, including brainmetastesis, including leptomeningeal disease and other systemicmetastesis. Some of the disclosed compounds also have the advantage ofhaving high microsomal stability. Compounds of the disclosure also mayhave favorable toxicity profiles related to other non-kinase targets.

In one aspect, the present disclosure provides a compound represented bythe following structural Formula (I):

or a pharmaceutically acceptable salt thereof, the definition of eachvariable is provided below.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier or diluentand one or more of the compounds disclosed herein, or a pharmaceuticallyacceptable salt thereof (a “pharmaceutical composition of thedisclosure”).

The present disclosure provides a method of treating a subject withcancer, comprising administering to the subject an effective amount of acompound of the disclosure (e.g., a compound of Formula (I)) or apharmaceutically acceptable salt thereof or a pharmaceutical compositionof the disclosure. In one embodiment, the cancer is non-small cell lungcancer. In another embodiment, the subject cancer has metastasized tothe brain. In another embodiment, the subject has brain metastasis fromnon-small cell lung cancer.

In one embodiment, the cancer to be treated has epidermal growth factorreceptor (EGFR) L858R mutation and/or exon 19 deletion mutation andT790M mutation. In another embodiment, the cancer to be treated mayfurther has epidermal growth factor receptor (EGFR) L858R mutationand/or exon 19 deletion mutation and the T790M mutation and the C797Smutation. In another embodiment, the cancer to be treated in either ofthe foregoing embodiments is lung cancer, e.g., non-small cell lungcancer. In a specific embodiment, the cancer is non-small cell lungcancer with brain metastasis.

The treatment method disclosed herein further comprises administering tothe subject an effective amount of afatinib, osimertinib, erlotinib, orgefitinib.

The present disclosure also provides a method of inhibiting epidermalgrowth factor receptor (EGFR) in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound of thedisclosure (e.g., a compound of Formula (I)) or a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition of thedisclosure.

The present disclosure also provides the use of an effective amount of acompound of the disclosure (e.g., a compound of Formula (I)), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of the disclosure, for the preparation of a medicament forthe treatment of cancers.

In another aspect, provided herein a compound of Formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of the disclosure for use in treating cancers.

DETAILED DESCRIPTION Definitions

The term “halo” as used herein means halogen and includes chloro,fluoro, bromo and iodo.

The term “alkyl” used alone or as part of a larger moiety, such as“alkoxy” or “haloalkyl” and the like, means saturated aliphaticstraight-chain or branched monovalent hydrocarbon radical. Unlessotherwise specified, an alkyl group typically has 1-4 carbon atoms, i.e.(C₁-C₄)alkyl. As used herein, a “(C₁-C₄)alkyl” group means a radicalhaving from 1 to 4 carbon atoms in a linear or branched arrangement.Examples include methyl, ethyl, n-propyl, iso-propyl, and the like.

The term “alkenyl” means an alkyl group in which one or morecarbon/carbon single bond is replaced by a double bond.

The term “alkoxy” means an alkyl radical attached through an oxygenlinking atom, represented by —O-alkyl. For example, “(C₁-C₄)alkoxy”includes methoxy, ethoxy, propoxy, and butoxy.

The term “aminoalkyl” means an alkyl group substituted —NH₂.

The terms “haloalkyl” and “haloalkoxy” means alkyl or alkoxy, as thecase may be, substituted with one or more halogen atoms.

The term “cycloalkyl” refers to a monocyclic saturated hydrocarbon ringsystem. Unless otherwise specified, cycloalkyl has from 3-6 carbonatoms. For example, a C₃-C₆ cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. Unless otherwise described, a “cycloalkyl”has from three to six carbon atoms.

The term “heterocyclyl” or “heterocyclic” refers to a radical of a 4- to12-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, andsulfur, including sulfoxide and sulfone (“4-12 membered heterocyclyl”).In some embodiments, a heterocyclyl group is a 4-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“4-10 membered heterocyclyl”). Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Aheterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”)or polycyclic (e.g., a bicyclic system (“bicyclic heterocyclyl”) ortricyclic system (“tricyclic heterocyclyl”); polycyclic ring systemsinclude fused, bridged, or spiro ring systems). Exemplary monocyclicheterocyclyl groups include azetidinyl, oxetanyl, thietanyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl,piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl,tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systemscan include heteroatoms in one or more rings in the polycyclic ringsystem. Substituents (e.g., R¹) may be present on one or more rings inthe polycyclic ring system.

A bridged bicyclic system has two non-aromatic rings containing from7-12 ring atoms (heterocyclyl or cycloalkyl) and which share three ormore atoms, with the two bridgehead atoms separated by a bridgecontaining at least one atom. “Bridged heterocyclyl” includes bicyclicor polycyclic hydrocarbon or aza-bridged hydrocarbon groups; examplesinclude 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.1]octanyl,6-oxa-2-azabicyclo[3.2.1]octanyl, 6-oxa-3-azabicyclo[3.2.1]octanyl, and8-oxa-3-azabicyclo[3.2.1]octanyl.

A fused bicyclic system has two non-aromatic rings (heterocyclyl orcycloalkyl) containing from 7-12 ring atoms and which share two adjacentring atoms. Examples of fused bicyclic systems includehexahydro-1H-furo[3,4-b]pyrrolyl, and hexahydro-1H-furo[3,4-c]pyrrolyl.

A spiro bicyclic system has two non-aromatic rings containing(heterocyclyl or cycloalkyl) from 7-12 ring atoms and which share onering atom. Examples of spiro bicyclic systems include1-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl,and 1,4-dioxa-9-azaspiro[5.5]undecan-9-yl.

Compounds of the Present Disclosure

Disclosed herein are embodiments of compounds having a general structureof Formula (I). These compounds are selective inhibitors of LRTM andLRTMCS EGFR. In contrast to other EGFR inhibitors such as osimertinibwhich binds EGFR irreversibly, the compounds of the disclosure arenon-covalent inhibitors.

In a first embodiment, the present disclosure provides a compoundrepresented by the following structural formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Z is O or NH;

each A¹, A², and A³ is independently N or CR; wherein each R isindependently H, halogen, or CH₃;

Ring A is 4-10 membered heterocyclyl;

each R¹ is independently halogen, CN, OH, NR_(a)R_(b), C₁-C₄ alkyl,C₁-C₄ alkoxy, C₃-C₆ cycloalkyl or —O—C₃-C₆ cycloalkyl, wherein thealkyl, alkoxy or cycloalkyl represented by R¹ or in the grouprepresented by R¹ is optionally substituted with 1 to 3 groups selectedfrom deuterium, halogen, OH, NR_(a)R_(b), C₁-C₂ alkyl, and C₁-C₂ alkoxy;

m is 0, 1, 2, 3, 4, 5, or 6;

R² is H, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₃-C₆ cycloalkyl,wherein the alkyl, alkoxy or cycloalkyl represented by R² is optionallysubstituted with 1 to 3 groups selected from halogen and OH;

R³ is H or methyl;

R⁴ is H or methyl; R⁵ is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl or 4-6membered monocyclic heterocyclyl, wherein the alkyl, cycloalkyl orheterocyclyl represented by R⁵ is optionally substituted with 1 to 3three groups selected from halogen, CN, OH, NR_(a)R_(b), C₁-C₂ alkyl,and C₁-C₂ alkoxy;

R⁶ is H or C₁-C₄ alkyl optionally substituted with 1 to 3 three groupsselected from halogen, CN, OH, NR_(a)R_(b), and C₁-C₂ alkoxy; and

each R_(a) and R_(b) is independently H or C₁-C₄ alkyl.

In an alterative first embodiment, the present disclosure provides acompound represented by the following structural formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Z is O or NH;

each A¹, A², and A³ is independently N or CR; wherein each R isindependently H, halogen, or CH₃;

Ring A is 4-10 membered heterocyclyl;

each R¹ is independently halogen, CN, OH, NR_(a)R_(b), C₁-C₄ alkyl,C₁-C₄ alkoxy, C₃-C₆ cycloalkyl or —O—C₃-C₆ cycloalkyl, wherein thealkyl, alkoxy or cycloalkyl represented by R¹ or in the grouprepresented by R¹ is optionally substituted with 1 to 3 groups selectedfrom deuterium, halogen, OH, NR_(a)R_(b), C₁-C₂ alkyl, and C₁-C₂ alkoxy;

m is 0, 1, 2, 3, 4, 5, or 6;

R² is H, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₃-C₆ cycloalkyl,wherein the alkyl, alkoxy or cycloalkyl represented by R² is optionallysubstituted with 1 to 3 groups selected from halogen, OR_(a), andNR_(a)R_(b);

R³ is H or methyl;

R⁴ is H or methyl;

R⁵ is H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl or 4-6 membered monocyclicheterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl representedby R⁵ is optionally substituted with 1 to 3 three groups selected fromhalogen, CN, OH, NR_(a)R_(b), C₁-C₂ alkyl, and C₁-C₂ alkoxy;

R⁶ is H or C₁-C₄ alkyl optionally substituted with 1 to 3 three groupsselected from halogen, CN, OH, NR_(a)R_(b), and C₁-C₂ alkoxy; and

each R_(a) and R_(b) is independently H or C₁-C₄ alkyl.

In a second embodiment, the present disclosure provides a compoundrepresented by structural formula (II-A), (II-B), (II-D), or (II-E):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the first embodiment.

In a third embodiment, the present disclosure provides a compoundrepresented by structural formula (II-A):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the first embodiment.

In a fourth embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein Z is O,wherein the remainder of the variables are as defined in the firstembodiment.

In a fifth embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein R² is H,fluorine, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₃-C₆ cycloalkyl, wherein thealkyl, alkoxy, or cycloalkyl represented by R² is optionally substitutedwith 1 to 3 groups selected from halogen and OH, wherein the remainderof the variables are as defined in the first or fourth embodiment. In analternative fifth embodiment, R² is H, fluorine, C₁-C₄ alkyl, C₁-C₄alkoxy, or C₃-C₆ cycloalkyl, wherein the alkyl, alkoxy or cycloalkylrepresented by R² is optionally substituted with 1 to 3 groups selectedfrom halogen, OH, and NH₂, wherein the remainder of the variables are asdefined in the first or fourth embodiment.

In a sixth embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein R⁶ is H,methyl, ethyl, C₁-C₂ haloalkyl, or C₁-C₂ aminoalkyl, wherein theremainder of the variables are as defined in the first, fourth, or fifthembodiment.

In a seventh embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein R⁵ H; isC₁-C₄ alkyl optionally substituted with 1 to 3 three groups selectedfrom halogen, CN, and NR_(a)R_(b); C₃-C₆ cycloalkyl; or 4-6 memberedmonocyclic heterocyclyl optionally substituted with C₁-C₄ alkyl; whereinR_(a) and R_(b) are each independently selected from H, methyl andethyl; and wherein the remainder of the variables are as defined in thefirst, fourth, fifth, or sixth embodiment.

In an eighth embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein Ring A is4-7 membered monocyclic heterocyclyl optionally substituted with 1-6 R¹,wherein the remainder of the variables are as defined in the first,fourth, fifth, sixth, or seventh embodiment.

In a ninth embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein Ring A is7-12 membered bicyclic heterocyclyl optionally substituted with 1-6 R¹,wherein the remainder of the variables are as defined in the first,fourth, fifth, sixth or seventh embodiment.

In a tenth embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein m is 1,2, 3, 4, or 5; each R¹ is independently halogen, CN, OH, NR_(a)R_(b),C₁-C₄ alkyl, C₁-C₄ alkoxy, —O—C₃-C₆ cycloalkyl, wherein the alkyl,alkoxy, or cycloalkyl represented by R¹ or in the group represented byR¹ is optionally substituted with 1 to 3 groups selected from deuterium,halogen, OH, NR_(a)R_(b), C₁-C₂ alkyl, and C₁-C₂ alkoxy; and wherein theremainder of the variables are as defined in the first, fourth, fifth,sixth, seventh, eighth, or ninth embodiment.

In an eleventh embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein R² is H,F, methyl, ethyl, isopropyl, CH(CH₃)CH₂F, CH(CH₃)CH₂OH, CF₃, OCH₃,OCH₂CH₃, or cyclopropyl, wherein the remainder of the variables are asdefined in the first, fourth, fifth, sixth, seventh, eighth, ninth, ortenth embodiment. In an alternative eleventh embodiment, the presentdisclosure provides a compound according to structural formula (I),(II-A), (II-B), (II-C), (II-D), or (II-E), or a pharmaceuticallyacceptable salt thereof, wherein R² is H, F, methyl, ethyl, isopropyl,CH(CH₃)CH₂F, CH(CH₃)CH₂OH, CF₃, OCH₃, OCH₂CH₃, C(CH₃)₂NH₂, orcyclopropyl, wherein the remainder of the variables are as defined inthe first, fourth, fifth (or alternative fifth), sixth, seventh, eighth,ninth, or tenth embodiment.

In a twelfth embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein R⁶ is H,CH₃, or CH₂NH₂, wherein the remainder of the variables are as defined inthe first, fourth, fifth, sixth, seventh, eighth, ninth, tenth, oreleventh embodiment.

In a thirteenth embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein Ring A isoptionally substituted with 1-6 R¹, and Ring A is pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, azepanyl,2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.1]octanyl,6-oxa-2-azabicyclo[3.2.1]octanyl, 6-oxa-3-azabicyclo[3.2.1]octanyl,8-oxa-3-azabicyclo[3.2.1]octanyl, hexahydro-1H-furo[3,4-b]pyrrolyl,hexahydro-1H-furo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl,1-oxa-7-azaspiro[3.5]nonan-7-yl, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl or1,4-dioxa-9-azaspiro[5.5]undecan-9-yl, wherein the remainder of thevariables are as defined in the first, fourth, fifth, sixth, seventh,tenth, eleventh, or twelfth embodiment.

In a fourteenth embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein at leastone R¹ is OH, C₁-C₄ alkoxy, or —O—C₃-C₆ cycloalkyl, wherein the alkoxyor cycloalkyl represented by R¹ or in the group represented by R¹ isoptionally substituted with 1 to 3 groups selected from deuterium,halogen, OH, NR_(a)R_(b), C₁-C₂ alkyl, and C₁-C₂ alkoxy, wherein theremainder of the variables are as defined in the first, fourth, fifth,sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenthembodiment.

In a fifteenth embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein each R¹is independently F, CN, OH, NH₂, CH₃, CH₂CH₃, CHF₂, CH(OH)CH₃, CH₂OH,CH₂NH₂, CH₂CH₂NH₂, OCH₃, OCD₃, OCH₂CH₂OH, OCH₂CH(OH)CH₃,OCH₂C(OH)(CH₃)₂, OCH₂CH₂OCH₃, OCH₂CH₂NH₂, OCH₂CH₂NHCH₃, OCH₂CH₂N(CH₃)₂,—O-cyclopropyl, NHCH₃, N(CH₃)₂, and wherein the remainder of thevariables are as defined in the first, fourth, fifth, sixth, seventh,eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenthembodiment. In one specific embodiment, each R¹ is independently F, OH,Me, Et, OMe, OCD₃, or OCH₂CH₂OH. In another specific embodiment, each R¹is independently F, OH, Me, or OCD₃.

In a sixteenth embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein

wherein the remainder of the variables are as defined in the first,fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth,thirteenth, fourteenth, or fifteenth embodiment. In one specificembodiment,

In a seventeenth embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein R² is Hor isopropyl, wherein the remainder of the variables are as defined inthe first, fourth, fifth, sixth, seventh, eighth, ninth, tenth,eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenthembodiment.

In an eighteenth embodiment, the present disclosure provides a compoundaccording to structural formula (I), (II-A), (II-B), (II-C), (II-D), or(II-E), or a pharmaceutically acceptable salt thereof, wherein Ring A ispiperidinyl optionally substituted with 1-6 R¹, wherein R² is H orisopropyl, wherein the remainder of the variables are as defined in thefirst, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh,twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenthembodiment.

In one embodiment, a compound of the present disclosure is any one ofthe compounds disclosed in the examples and Table 1, or apharmaceutically acceptable salt thereof.

The term “pharmaceutically-acceptable salt” refers to a pharmaceuticalsalt that is, within the scope of sound medical judgment, suitable foruse in contact with the tissues of humans and lower animals withoutundue toxicity, irritation, and allergic response, and is commensuratewith a reasonable benefit/risk ratio. Pharmaceutically-acceptable saltsare well known in the art. For example, S. M. Berge et al. describespharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

Included in the present teachings are pharmaceutically acceptable saltsof the compounds disclosed herein. Compounds having basic groups canform pharmaceutically acceptable salts with pharmaceutically acceptableacid(s). Suitable pharmaceutically acceptable acid addition salts of thecompounds described herein include salts of inorganic acids (such ashydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, andsulfuric acids) and of organic acids (such as acetic, benzenesulfonic,benzoic, ethanesulfonic, methanesulfonic, and succinic acids). Compoundsof the present teachings with acidic groups such as carboxylic acids canform pharmaceutically acceptable salts with pharmaceutically acceptablebase(s). Suitable pharmaceutically acceptable basic salts includeammonium salts, alkali metal salts (such as sodium and potassium salts)and alkaline earth metal salts (such as magnesium and calcium salts).

Compounds having one or more chiral centers can exist in variousstereoisomeric forms, i.e., each chiral center can have an R or Sconfiguration, or can be a mixture of both. Stereoisomers are compoundsthat differ only in their spatial arrangement. Stereoisomers include alldiastereomeric and enantiomeric forms of a compound. Enantiomers arestereoisomers that are mirror images of each other. Diastereomers arestereoisomers having two or more chiral centers that are not identifcaland are not mirror images of each other.

When the stereochemical configuration at a chiral center in a compoundhaving one or more chiral centers is depicted by its chemical name(e.g., where the configuration is indicated in the chemical name by “R”or “S”) or structure (e.g., the configuration is indicated by “wedge”bonds), the enrichment of the indicated configuration relative to theopposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or99.9% (except when the designation “rac” or “racemate accompanies thestructure or name, as explained in the following two paragraphs).“Enrichment of the indicated configuration relative to the oppositeconfiguration” is a mole percent and is determined by dividing thenumber of compounds with the indicated stereochemical configuration atthe chiral center(s) by the total number of all of the compounds withthe same or opposite stereochemical configuration in a mixture.

When the stereochemical configuration at a chiral center in a compoundis depicted by chemical name (e.g., where the configuration is indicatedin the name by “R” or “S”) or structure (e.g., the configuration isindicated by “wedge” bonds) and the designation “rac” or “racemate”accompanies the structure or is designated in the chemical name, aracemic mixture is intended.

When two stereoisomers are depicted by their chemical names orstructures, and the chemical names or structures are connected by an“and”, a mixture of the two stereoisomers is intended.

When two stereoisomers are depicted by their chemical names orstructures, and the names or structures are connected by an “or”, one orthe other of the two stereoisomers is intended, but not both.

When a disclosed compound having a chiral center is depicted by astructure without showing a configuration at that chiral center, thestructure is meant to encompass the compound with the S configuration atthat chiral center, the compound with the R configuration at that chiralcenter, or the compound with a mixture of the R and S configuration atthat chiral center. When a disclosed compound having a chiral center isdepicted by its chemical name without indicating a configuration at thatchiral center with “S” or “R”, the name is meant to encompass thecompound with the S configuration at that chiral center, the compoundwith the R configuration at that chiral center or the compound with amixture of the R and S configuration at that chiral center.

A racemic mixture means a mixture of 50% of one enantiomer and 50% ofits corresponding enantiomer. The present teachings encompass allenantiomerically-pure, enantiomerically-enriched, diastereomericallypure, diastereomerically enriched, and racemic mixtures, anddiastereomeric mixtures of the compounds disclosed herein.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

“Peak 1” in the Experimental section refers to an intended reactionproduct compound obtained from a chromatography separation/purificationthat elutes earlier than a second intended reaction product compoundfrom the same preceding reaction. The second intended product compoundis referred to as “peak 2”.

When a disclosed compound is designated by a name or structure thatindicates a single enantiomer, unless indicated otherwise, the compoundis at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (alsoreferred to as “enantiomerically pure”). Optical purity is the weight inthe mixture of the named or depicted enantiomer divided by the totalweight in the mixture of both enantiomers.

When the stereochemistry of a disclosed compound is named or depicted bystructure, and the named or depicted structure encompasses more than onestereoisomer (e.g., as in a diastereomeric pair), it is to be understoodthat, unless otherwise indicated, one of the encompassed stereoisomersor any mixture of the encompassed stereoisomers are included. It is tobe further understood that the stereoisomeric purity of the named ordepicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% byweight. The stereoisomeric purity in this case is determined by dividingthe total weight in the mixture of the stereoisomers encompassed by thename or structure by the total weight in the mixture of all of thestereoisomers.

In the compounds of the disclosure, any position specifically designatedas “D” or “deuterium” is understood to have deuterium enrichment at 50,80, 90, 95, 98 or 99%. “Deuterium enrichment” is a mole percent and isdetermined by dividing the number of compounds with deuterium at theindicated position by the total number of all of the compounds. When aposition is designated as “H” or “hydrogen”, the position has hydrogenat its natural abundance. When a position is silent as to whetherhydrogen or deuterium is present, the position has hydrogen at itsnatural abundance. One specific alternative embodiment is directed to acompound of the disclosure having deuterium enrichment of at least 5,10, 25, 50, 80, 90, 95, 98 or 99% at one or more positions notspecifically designated as “D” or “deuterium”.

As used herein, many moieties (e.g., alkyl, alkoxy, cycloalkyl orheterocyclyl) are referred to as being either “substituted” or“optionally substituted”. When a moiety is modified by one of theseterms, unless otherwise noted, it denotes that any portion of the moietythat is known to one skilled in the art as being available forsubstitution can be substituted, which includes one or moresubstituents. Where if more than one substituent is present, then eachsubstituent may be independently selected. Such means for substitutionare well-known in the art and/or taught by the instant disclosure. Theoptional substituents can be any substituents that are suitable toattach to the moiety.

Compounds of the disclosure are selective EGFR inhibitors. As usedherein, the term “selective EGFR inhibitor” means a compound whichselectively inhibits certain mutant EGFR kinases over wild-type EGFR andthe kinome. Said another way, a selective EGFR inhibitor has no or lowactivity against wild-type EGFR and the kinome. A selective EGFRinhibitor's inhibitory activity against certain mutant EGFR kinases ismore potent in terms of IC₅₀ value (i.e., the IC₅₀ value issubnanomolar) when compared with its inhibitory activity againstwild-type EGFR and many other kinases. Potency can be measured usingknown biochemical assays.

Some compounds of the disclosure have the advantage of good penetrationof the brain. The ability of a particular compound to cross the BBB andpenetrate the brain can be assessed using a variety of known methods orcombinations of such methods. One in vitro method that is frequentlyused to predict a compound's in vivo brain penetration is P-gp effluxratio. P-glycoprotein (P-gp) is expressed at the blood-brain barrier(BBB) and restricts the penetration of its substrates into the centralnervous system (CNS). Compounds that are found to be good P-gpsubstrates in vitro (i.e., have a high efflux ratio) are predicted tohave poor in vivo brain penetration. In order to measure the P-gp effluxratio, Madin-Darby canine kidney cells overexpressing P-gp (MDCK-MDR1cells) the apparent apical to basolateral permeability (Papp[A-B]) andthe apparent basolateral to apical permeability (Papp[B-A]) forcompounds is determined. The P-gp efflux ratio is a measure of the ratioof Papp[B-A]/Papp[A-B]. In some embodiments, a compound of thedisclosure has a P-gp efflux ratio of less than 2, less than 3, lessthan 4, less than 5.

Some compounds of the disclosure have the advantage of good metabolicstability. One indicator of good metabolic stability is high microsomalstability. Hepatic metabolism is a predominant route of elimination forsmall molecule drugs. The clearance of compounds by hepatic metabolismcan be assessed in vitro using human liver microsomes (HLMs) or humanhepatocytes. Compounds are incubated with HLMs plus appropriateco-factors or human hepatocytes and compound depletion is measured todetermine an in vitro intrinsic clearance (Clint). The Clint is scaledto total body clearance (CL), and a hepatic extraction ratio (ER) isdetermined by dividing CL to standard human hepatic blood flow.Compounds that have a low hepatic extraction ratio are considered tohave good metabolic stability. In some embodiments, a compound of thedisclosure has a calculated ER of <0.3, <0.4, <0.5, <0.6.

Pharmaceutical Compositions

Pharmaceutical compositions of the disclosure (also referred to hereinas the “disclosed pharmaceutical compositions”) comprise one or morepharmaceutically acceptable carrier(s) or diluent(s) and a compound ofthe disclosure (e.g., a compound of Formula (I)), or a pharmaceuticallyacceptable salt thereof.

“Pharmaceutically acceptable carrier” and “pharmaceutically acceptablediluent” refer to a substance that aids the formulation and/oradministration of an active agent to and/or absorption by a subject andcan be included in the pharmaceutical compositions of the disclosurewithout causing a significant adverse toxicological effect on thesubject. Non-limiting examples of pharmaceutically acceptable carriersand/or diluents include water, NaCl, normal saline solutions, lactatedRinger's, normal sucrose, normal glucose, binders, fillers,disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions(such as Ringer's solution), alcohols, oils, gelatins, carbohydratessuch as lactose, amylose or starch, hydroxymethycellulose, fatty acidesters, polyvinyl pyrrolidine, and colors, and the like. Suchpreparations can be sterilized and, if desired, mixed with auxiliaryagents such as lubricants, preservatives, stabilizers, wetting agents,emulsifiers, salts for influencing osmotic pressure, buffers, coloring,and/or aromatic substances and the like that do not deleteriously reactwith or interfere with the activity of the compounds provided herein.One of ordinary skill in the art will recognize that otherpharmaceutical excipients are suitable for use with disclosed compoundsor pharmaceutically acceptable salts thereof.

The pharmaceutical compositions of the disclosure optionally include oneor more pharmaceutically acceptable carriers and/or diluents therefor,such as lactose, starch, cellulose and dextrose. Other excipients, suchas flavoring agents, sweeteners, and preservatives, such as methyl,ethyl, propyl and butyl parabens, can also be included. More completelistings of suitable excipients can be found in the Handbook ofPharmaceutical Excipients (5^(th) Ed., Pharmaceutical Press (2005)). Aperson skilled in the art would know how to prepare formulationssuitable for various types of administration routes. Conventionalprocedures and ingredients for the selection and preparation of suitableformulations are described, for example, in Remington's PharmaceuticalSciences (2003-20th edition) and in The United States Pharmacopeia: TheNational Formulary (USP 24 NF19) published in 1999. The carriers,diluents and/or excipients are “acceptable” in the sense of beingcompatible with the other ingredients of the pharmaceutical compositionand not deleterious to the recipient thereof.

Methods of Treatment

The present disclosure provides a method of inhibiting certain mutantforms of epidermal growth factor receptor (EGFR) in a subject in needthereof, comprising administering to the subject an effective amount ofa compound disclosed herein, a pharmaceutically acceptable salt thereofor a pharmaceutical composition disclosed herein. Mutant forms of EGFRinclude for example, EGFR with LRTMCS mutation (the exon 19 deletion(del19) or exon 21 (L858R) substitution mutation, T790M mutation, andC797S mutation). Subjects “in need of inhibiting EGFR” are those havinga disease for which a beneficial therapeutic effect can be achieved byinhibiting at least one mutant EGFR, e.g., a slowing in diseaseprogression, alleviation of one or more symptoms associated with thedisease or increasing the longevity of the subject in view of thedisease.

In some embodiments, the disclosure provides a method of treating adisease/condition/or cancer associated with or modulated by mutant EGFR,wherein the inhibition of the mutant EGFR is of therapeutic benefit,including but not limited to the treatment of cancer in a subject inneed thereof. The method comprises administering to the subject aneffective amount of a compound disclosed herein, a pharmaceuticallyacceptable salt thereof, or pharmaceutical composition disclosed herein.

In another embodiment, the disclosure provides a method of treating asubject with cancer, comprising administering to the subject aneffective amount of a compound disclosed herein, a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition disclosedherein. Cancers to be treated according to the disclosed methods includelung cancer, colon cancer, urothelial cancer, breast cancer, prostatecancer, brain cancers, ovarian cancer, gastric cancer, pancreaticcancer, head and neck cancer, bladder cancer, and mesothelioma,including metastasis (in particular brain metastasis) of all cancerslisted. Typically, the cancer is characterized by at one or more EGFRmutations described herein. In a specific embodiment, the cancer hasprogressed on or after EGFR tyrosine kinase inhibitor (TKI) Therapy. Ina specific embodiment, the disease has progressed on or after first lineosimertinib.

In a specific embodiment, the cancer to be treated is lung cancer. In amore specific embodiment, the cancer is non-small cell lung cancer(NSCLC). In some embodiments, the lung cancer is locally advanced ormetastatic NSCLC, NSCLC adenocarcinoma, NSCLC with squamous histologyand NSCLC with non-squamous histology. In another embodiment, the lungcancer is NSCLC adenocarcinoma. In another specific embodiment, the lungcancer (or non-small cell lung cancer) has metastasized to the brain.

In another embodiment, the disease/condition/or cancer associated withor modulated by mutant EGFR that is characterized by an EGFR genotypeselected from genotypes 1-17 according the Table below (del18=Exon 18deletion, specifically, e.g., del E709_J710 insD; del19=Exon 19deletion, specifically, e.g., delE746_A750 (most common),delE746_S752insV, del747A750insP, delL747_P753insS, and delS752_1759;ex20ins—Exon 20 insertion, specifically, e.g., D761-E762insX,A763-Y764insX, Y764-V765insX, V765-M766insX, A767-S768insX,S768-D769insX, V769-D770insX, N771-P772insX, P772-H773insX,H773-V774insX, and V774-C775insX):

EGFR Genotype 1 EGFR del19 2 EGFR del19 T790M 3 EGFR del19 C797S 4 EGFRdel19 C797X (C797G or C797N) 5 EGFR del19 T790M C797S 6 EGFR del19 T790MC797S Q791P 7 EGFR del19 T790M (C797G or C797N) 8 EGFR del19 L792X(L792F, L792H or L792Y) 9 EGFR del19 T790M L792X (L792F, L792H, orL792Y) 10 EGFR del19 G796R (G796S) 11 EGFR del19 T790M G796R (G796S)C797S L792X (L792F, L792H or L792Y) 12 EGFR del19 L792R (L792V or L792P)13 EGFR del19 L718Q (L718V) 14 EGFR del19 T790M L718Q (L718V) L792X(L792F, L792H or L792Y) 15 EGFR del19 T790M G796R (G796S) 16 EGFR del19T790M L792R (L792V or L792P) 17 EGFR del19 T790M L718Q (L718V) 18 EGFRdel19 T790M C797S L718Q (L718V) 19 EGFR del19 G724S 20 EGFR del19 T790MG724S 21 EGFR del19 S768I (SV768IL) 22 EGFR del19 T790M S768I (SV768IL)23 EGFR del19 T790M C797S/G L792X (L792F, L792H, L792R, or L792Y) 24EGFR del 19 V834L 25 EGFR del 19 T790M V834L 27 EGFR del19 T790M L792X(L792F, L792H, L792R, or L792Y) 28 EGFR del19 C797S L718Q (L718V) 29EGFR del19 L718Q (L718V) A750P 30 EGFR del19 T790M L718Q (L718V) A750PL792V G796R 31 EGFR L858R 32 EGFR L858R T790M 33 EGFR L858R C797S 34EGFR L858R C797X (797G or C797N) 35 EGFR L858R T790M C797S 36 EGFR L858RT790M C797S Q791P 37 EGFR L858R T790M C797X (C797G or C797N) 38 EGFRL858R L792X (L792F, L792H or L792Y) 39 EGFR L858R T790M L792X (L792F,L792H or L792Y) 40 EGFR L858R G796R (G796S) 41 EGFR L858R T790M G796R(G796S) C797S L792X (L792F, L792H or L792Y) 42 EGFR L858R L792R (L792Vor L792P) 43 EGFR L858R L718Q (L718V) 44 EGFR L858R T790M G796R (G796S)45 EGFR L858R T790M L792R (L792V or L792P) 46 EGFR L858R T790M L718Q(L718V) 47 EGFR L858R T790M C797S L718Q (L718V) 48 EGFR L858R T790ML718Q (L718V) L792X (L792F, L792H or L792Y) 49 EGFR L858R G724S 50 EGFRL858R T790M G724S 51 EGFR L858R S768I (SV768IL) 52 EGFR L858R T790MS768I (SV768IL) 53 EGFR L858R T790M C797S/G L792X (L792F, L792H, L792R,or L792Y) 54 EGFR L858R V834L 55 EGFR L858R T790M V834L 57 EGFR L858RT790M L792X (L792F, L792H, L792R, or L792Y) 58 EGFR L858R C797S L718Q(L718V) 59 EGFR L858R L718Q (L718V) A750P 60 EGFR L858R T790M L718Q(L718V) A750P L792V G796R 61 EGFR L861Q 62 EGFR L861Q T790M 63 EGFRL861Q T790M C797S/G/N 64 EGFR L861Q C797S/G/N 65 EGFR del18 66 EGFRG719X (G719A, G719S, G719C, G719R, G719D, or G719V) 67 EGFR E709X(E709K, E709H, or E709A) 68 EGFR E709X (E709K, E709H, or E709A) (G719A,G719S, G719C, G719D, G719R, or G719V) 69 EGFR G719X (G719A, G719S,G719C, G719D, G719R, or G719V) S768I 70 EGFR ex20ins 71 EGFR ex20insL718Q 72 EGFR ex20ins T790M 73 EGFR ex20ins C797S 74 EGFR S7681I 75 EGFRT790M 76 EGFR T790M C797S/G L792X (L792F, L792H, L792R, or L792Y)

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR del19.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR del19 T790M.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR del19 C797S.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR del19 C797X (C797G or C797N).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR del19 T790M C797S.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR del19 T790M (C797G or C797N).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt, or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR del19 L792X (L792F, L792H or L792Y).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof, or pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR del19 T790M L792X (L792F, L792H,or L792Y).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof, or pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR del19 G796R (G796S).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof, or pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR del19 L792R (L792V or L792P).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof, or pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR del19 L718Q (L718V).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof, or pharmaceutical composition described herein ischaracterized by EGFR comprising EGFR del19 T790M G796R (G796S).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof, or pharmaceutical composition described herein ischaracterized by EGFR comprising EGFR del19 T790M L792R (L792V orL792P).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or pharmaceutical composition described herein ischaracterized by EGFR comprising EGFR del19 T790M L718Q (L718V).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR L858R.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR L858R T790M.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR L858R C797S.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR L858R C797X (797G or C797N).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR L858R T790M C797S.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR L858R T790M C797X (797G or C797N).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR L858R L792X (L792F, L792H orL792Y).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR L858R L790M L792X (L792F, L792H orL792Y).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR L858R G796R (G796S).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR L858R L792R (L792V or L792P).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR L858R L718Q (L718V).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR L858R T790M G796R (G796S).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR L858R T790M L792R (L792V orL792P).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt thereof or pharmaceutical composition disclosed herein ischaracterized by EGFR comprising EGFR L858R T790M L718Q (L718V).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR del18.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR G719X (G719A, G719S, G719C, G719R, G719D, orG719V).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR E709X (E709K, E709H, or E709A).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR E709X (E709K, E709H, or E709A) (G719A, G719S,G719C, G719D, G719R, or G719V).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR G719X (G719A, G719S, G719C, G719D, G719R, orG719V) S768I.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR ex20ins.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR ex20ins L718Q.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR ex20ins T790M.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR ex20ins C797S.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR S7681I.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR T790M.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR comprising EGFR T790M C797S/G L792X (L792F, L792H, L792R, orL792Y).

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby an EGFR genotype selected from genotypes 1-17.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR mutations that confer resistance to osimertinib.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR mutations that confer resistance to afatinib.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR mutations that confer resistance to dacomitinib.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR mutations that confer resistance to gefitinib.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR mutations that confer resistance to erlotinib.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR mutations that confer resistance to osimertinib and afatinib.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR mutations that confer resistance to osimertinib and dacomitinib.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR mutations that confer resistance to osimertinib and gefitinib.

In another embodiment, the disease/condition/or cancer (e.g., NSCLC)being treated with a disclosed compound, a pharmaceutically acceptablesalt or a pharmaceutical composition disclosed herein is characterizedby EGFR mutations that confer resistance to osimertinib and erlotinib.

Another embodiment is the treatment a subject with metastatic NSCLC withtumors harboring activating Exon 19 Deletion or L858R EGFR mutations aswell as a resistance mutation disclosed herein as detected by anapproved molecular testing methodology. Another embodiment is adisclosed compound used in combination with a 1^(st) or 3^(rd)generation TKI indicated for the treatment of subject with metastaticNSCLC with tumors harboring T790M and C797S mutations as detected by anapproved test, and whose disease has progressed on or after at least 2prior EGFR TKI therapies.

Another embodiment is a disclosed compound for the treatment of subjectswith metastatic NSCLC whose disease with on-target EGFR resistance hasprogressed on or after any EGFR TKI. In a specific embodiment, thedisclosed compound is used in combination with a 1^(st) or 3^(rd)generation TKI indicated for the treatment of subject with metastaticNSCLC.

Another embodiment is a disclosed compound for the treatment of subjectswith metastatic EGFR C797S mutation-positive NSCLC as detected by anapproved molecular test, whose disease has progressed on or afterfirst-line osimertinib. In a specific embodiment, the disclosed compoundis used in combination with a 1^(st) or 3^(rd) generation TKI indicatedfor the treatment of subject with metastatic NSCLC.

In a particular embodiment, the deletions, mutations, and insertionsdisclosed herein are detected by an FDA-approved test.

A person of ordinary skill in the art can readily determine the certainEGFR alterations a subject possesses in a cell, cancer, gene, or geneproduct, e.g., whether a subject has one or more of the mutations ordeletions described herein using a detection method selected from thoseknown in the art such as hybridization-based methods,amplification-based methods, microarray analysis, flow cytometryanalysis, DNA sequencing, next-generation sequencing (NGS), primerextension, PCR, in situ hybridization, fluorescent in situhybridization, dot blot, and Southern blot.

To detect one or more EGFR deletions and/or mutations, a primary tumorsample, circulating tumor DNA (ctDNA), circulating tumor cells (CTC),and/or circulating exosomes may be collected from a subject. The samplesare processed, the nucleic acids are isolated using techniques known inthe art, then the nucleic acids are sequenced using methods known in theart. Sequences are then mapped to individual exons, and measures oftranscriptional expression (such as RPKM, or reads per kilobase permillion reads mapped), are quantified. Raw sequences and exon array dataare available from sources such as TCGA, ICGC, and the NCBI GeneExpression Omnibus (GEO). For a given sample, individual exoncoordinates are annotated with gene identifier information, and exonsbelonging to kinase domains are flagged. The exon levels are thenz-score normalized across all tumors samples.

The compounds of the disclosure, pharmaceutically acceptable saltsthereof or pharmaceutical compositions disclosed herein may be used fortreating to a subject who has become refractory to treatment with one ormore other EGFR inhibitors. “Refractory” means that the subject's cancerpreviously responded to drugs but later responds poorly or not at all.In some embodiments, the subject has become refractory to one or morefirst generation EGFR inhibitors such as erlotinib, gefitinib, icotinibor lapatinib. In some embodiments, the subject has been becomerefractory to treatment with one or more second generation EGFRinhibitors such as afatinib, dacomitinib, poziotinib, or neratinib. Insome embodiments the subject has become refractory to treatment with oneor more first generation inhibitors and one or more second generationinhibitors. In some embodiments, the subject has become refractory totreatment with one or more third generation inhibitors such asosimertinib, nazartinib, or avitinib. In one embodiment, the subject hasbecome refractory to treatment with one or more first generation EGFRinhibitors and one or more third generation EGFR inhibitors. In someembodiments, the subject has become refractory to treatment with one ormore second generation EGFR inhibitors and one or more third generationEGFR inhibitors. In some embodiments, the subject has become refractoryto treatment with one or more first generation inhibitors, and one ormore third generation EGFR inhibitors.

Combinations

The compounds of the disclosure, pharmaceutically acceptable saltsthereof, or pharmaceutical compositions disclosed herein can be used incombination with one or more additional pharmacologically activesubstances. For example, the disclosure includes methods of treating acondition/disease/or cancer comprising administering to a subject inneed thereof a compound of the disclosure or a pharmaceuticallyacceptable salt or a pharmaceutical composition disclosed herein thereofin combination with an EGFR (or EGFR mutant) inhibitor, such asafatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib,neratinib, gefitinib JBJ-04-125-02, alflutinib (AST 2818), almonertinib(HS10296), BBT-176, BI-4020, CH7233163, gilitertinib, JND-3229,lazertinib, nazartinib (EGF 816), PCC-0208027, rezivertinib (BPI-7711),TQB3804, zorifertinib (AZ-3759), or DZD9008; an EGFR antibody such ascetuximab, panitumumab, necitumumab, HLX07, JMT101; or a bispecific EGFRand MET antibody (e.g., amivantamab ((JNJ-61186372, JNJ-372)). For thetreatment of cancer e.g., NSCLC using a compound of the disclosure orpharmaceutically acceptable salt thereof or pharmaceutical compositiondisclosed herein in combination with a first line therapy, for example afirst, second, or third generation EGFR inhibitor (i.e., as an initialtreatment before the cancer has become refractory) may forestall ordelay the cancer from becoming refractory. Typically, the cancer ischaracterized by one of the EGFR genotypes described herein.

Alternatively, a compound of the disclosure, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition disclosed hereincan be administered in combination with other anti-cancer agents thatare not EGFR inhibitors e.g., in combination with MEK, including mutantMEK inhibitors (trametinib, cobimtetinib, binimetinib, selumetinib,refametinib); c-MET, including mutant c-Met inhibitors (savolitinib,cabozantinib, foretinib, glumetinib, tepotinib) and MET antibodies(emibetuzumab, telisotuzumab vedotin (ABBV 339)); mitotic kinaseinhibitors (CDK4/6 inhibitors such as palbociclib, ribociclib,abemacicilb, GIT38); anti-angiogenic agents e.g., bevacizumab,nintedanib; apoptosis inducers such as Bcl-2 inhibitors e.g, venetoclax,obatoclax, navitoclax, palcitoclax (APG-1252), and Mc1-1 inhibitorse.g., AZD-5991, AMG-176, S-64315; mTOR inhibitors e.g, rapamycin,temsirolimus, everolimus, ridoforolimus; RET inhibitors, likepralsetinib and selpercatinib, and PI3K inhibitors dactolisib (BEZ235),pictilisib (GDC-0941), LY294002, idelalisib (CAL-101); JAK inhibitors(e.g., AZD4205, itacitinib), Aurora A inhibitors (e.g., alisertib);BCR/ABL and/or Src family tyrosine kinase inhibitors (e.g., dasatinib);VEGF inhibitors (e.g., MP0250; ramucirumab); multi-kinase proteininhibitors (e.g., anlotinib, midostaurin); PARP inhibitors (e.g.,niraparib); platinum therapies (e.g., cisplatin (CDDP), carboplatin(CBDCA), or nedaplatin (CDGP)); PD-L1 inhibitors (e.g., durvalumab (MEDI4736)); HER2/neu receptor inhibitors (e.g., trastuzumab); anti-HER2 oranti-HER3 antibody-drug conjugates (e.g., patritumab deruxtecan(U3-1402), trastuzumab emtansine); or immunogene therapy (e.g.,oncoprex).

A “subject” is a human in need of treatment.

Methods of Administration and Dosage Forms

The precise amount of compound administered to provide an “effectiveamount” to the subject will depend on the mode of administration, thetype, and severity of the cancer, and on the characteristics of thesubject, such as general health, age, sex, body weight, and tolerance todrugs. The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors. When administered in combinationwith other therapeutic agents, e.g., when administered in combinationwith an anti-cancer agent, an “effective amount” of any additionaltherapeutic agent(s) will depend on the type of drug used. Suitabledosages are known for approved therapeutic agents and can be adjusted bythe skilled artisan according to the condition of the subject, the typeof condition(s) being treated and the amount of a compound of Formula(I) being used by following, for example, dosages reported in theliterature and recommended in the Physician's Desk Reference (57th Ed.,2003).

“Treating” or “treatment” refers to obtaining a desired pharmacologicaland/or physiological effect. The effect can be therapeutic, whichincludes achieving, partially or substantially, one or more of thefollowing results: partially or substantially reducing the extent of thedisease, condition or cancer; ameliorating or improving a clinicalsymptom or indicator associated with the disease, condition or cancer;delaying, inhibiting or decreasing the likelihood of the progression ofthe disease, condition or cancer; or decreasing the likelihood ofrecurrence of the disease, condition or cancer.

The term “effective amount” means an amount when administered to thesubject which results in beneficial or desired results, includingclinical results, e.g., inhibits, suppresses or reduces the symptoms ofthe condition being treated in the subject as compared to a control. Forexample, a therapeutically effective amount can be given in unit dosageform (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg toabout 5 grams per day; and in another alternatively from 10 mg to 1 gramper day).

The terms “administer”, “administering”, “administration”, and the like,as used herein, refer to methods that may be used to enable delivery ofcompositions to the desired site of biological action. These methodsinclude, but are not limited to, intraarticular (in the joints),intravenous, intramuscular, intratumoral, intradermal, intraperitoneal,subcutaneous, orally, topically, intrathecally, inhalationally,transdermally, rectally, and the like. Administration techniques thatcan be employed with the agents and methods described herein are foundin e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (currentedition), Mack Publishing Co., Easton, Pa.

In addition, a compound of the disclosure, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition of the disclosure can beco-administered with other therapeutic agents. As used herein, the terms“co-administration”, “administered in combination with”, and theirgrammatical equivalents, are meant to encompass administration of two ormore therapeutic agents to a single subject, and are intended to includetreatment regimens in which the agents are administered by the same ordifferent route of administration or at the same or different times. Insome embodiments the one or more compounds of the disclosure, apharmaceutically acceptable salt thereof or a pharmaceutical compositionof the disclosure will be co-administered with other agents. These termsencompass administration of two or more agents to the subject so thatboth agents and/or their metabolites are present in the subject at thesame time. They include simultaneous administration in separatecompositions, administration at different times in separatecompositions, and/or administration in a composition in which bothagents are present. Thus, in some embodiments, the compounds describedherein and the other agent(s) are administered in a single composition.In some embodiments, the compounds described herein and the otheragent(s) are admixed in the composition.

The particular mode of administration and the dosage regimen will beselected by the attending clinician, taking into account the particularsof the case (e.g. the subject, the disease, the disease state involved,the particular treatment). Treatment can involve daily or multi-daily orless than daily (such as weekly or monthly etc.) doses over a period ofa few days to months, or even years. However, a person of ordinary skillin the art would immediately recognize appropriate and/or equivalentdoses looking at dosages of approved compositions for treating a diseaseusing the disclosed EGFR inhibitors for guidance.

The compounds of the disclosure or a pharmaceutically acceptable saltthereof can be administered to a patient in a variety of forms dependingon the selected route of administration, as will be understood by thoseskilled in the art. The compounds of the present teachings may beadministered, for example, by oral, parenteral, buccal, sublingual,nasal, rectal, patch, pump or transdermal administration and thepharmaceutical compositions formulated accordingly. Parenteraladministration includes intravenous, intraperitoneal, subcutaneous,intramuscular, transepithelial, nasal, intrapulmonary, intrathecal,rectal and topical modes of administration. Parenteral administrationcan be by continuous infusion over a selected period of time.

The pharmaceutical composition of the disclosure is formulated to becompatible with its intended route of administration. In an embodiment,the composition is formulated in accordance with routine procedures as apharmaceutical composition adapted for intravenous, subcutaneous,intramuscular, oral, intranasal, or topical administration to humanbeings. In preferred embodiments, the pharmaceutical composition isformulated for intravenous administration.

Typically, for oral therapeutic administration, a compound of thedisclosure or a pharmaceutically acceptable salt thereof may beincorporated with excipient and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like.

Typically for parenteral administration, solutions of a compound of thedisclosure can generally or a pharmaceutically acceptable salt thereofbe prepared in water suitably mixed with a surfactant such ashydroxypropylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, DMSO and mixtures thereof with or withoutalcohol, and in oils. Under ordinary conditions of storage and use,these preparations contain a preservative to prevent the growth ofmicroorganisms.

Typically, for injectable use, sterile aqueous solutions or dispersionof, and sterile powders of, a compound of the disclosure for theextemporaneous preparation of sterile injectable solutions ordispersions are appropriate.

The following examples are intended to be illustrative and are notintended to be limiting in any way to the scope of the disclosure.

EXEMPLIFICATION Examples Preparation of Exemplary Compounds Definitions

TsOH 4-methylbenzenesulfonic acidTEA triethylamineTHF tetrahydrofuranMSCl methanesulfonyl chlorideDCM dichloromethaneNH4Cl ammonium chlorideMgSO4 magnesium sulfateNaN3 sodium azideDMF dimethyl formamideEA ethyl acetateNa2SO4 sodium sulfateMeOH methanolN2 nitrogenH2 hydrogenLiAlH4 lithium aluminum hydrideNaHCO3 sodium bicarbonateCbzCl benzyl carbonochloridatePE petroleum etherDAST N-ethyl-N-(trifluoro-sulfanyl)ethanamineHCl hydrochlorideACN acetontirileDIPEA diisopropylethylamineDMSO dimethylsulfoxideDMA dimethylacetamideh hsHPLC high performance liquid chromatographymin minutes

C Celsius

IC₅₀ inhibitory concentration 50%IPA isopropyl alcoholMTBE methyl tert-butyl etherrt room temperatureTFA trifluoroacetic acid

Methods for preparing compounds of the invention can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), intermediates, orproducts at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in Wuts and Greene,Protective Groups in Organic Synthesis, 5th ed., John Wiley & Sons: NewJersey, (2014), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance (NMR) spectroscopy (e.g., ¹Hor ¹³C), infrared (IR) spectroscopy, spectrophotometry (e.g.,UV-visible), mass spectrometry (MS), or by chromatographic methods suchas high performance liquid chromatography (HPLC) or thin layerchromatography (TLC). Analytical instruments and methods for compoundcharacterization:

LC-MS: The liquid chromatography-mass spectrometry (LC-MS) data (sampleanalyzed for purity and identity) were obtained with an Agilentmodel-1260 LC system using an Agilent model 6120 mass spectrometerutilizing ES-API ionization fitted with an Agilent Poroshel 120 (EC-C18,2.7 um particle size, 3.0×50 mm dimensions) reverse-phase column at 22.4degrees Celsius. The mobile phase consisted of a mixture of solvent 0.1%formic acid in water and 0.1% formic acid in acetonitrile. A constantgradient from 95% aqueous/5% organic to 5% aqueous/95% organic mobilephase over the course of 4 minutes was utilized. The flow rate wasconstant at 1 mL/min.

Alternatively, the liquid chromatography-mass spectrometry (LC-MS) data(sample analyzed for purity and identity) were obtained with a ShimadzuLCMS system using an Shimadzu LCMS mass spectrometer utilizing ESIionization fitted with an Agilent (Poroshel HPH-C18 2.7 um particlesize, 3.0×50 mm dimensions) reverse-phase column at 22.4 degreesCelsius. The mobile phase consisted of a mixture of solvent 5 mM NH₄HCO₃(or 0.05% TFA) in water and acetonitrile. A constant gradient from 90%aqueous/10% organic to 5% aqueous/95% organic mobile phase over thecourse of 2 minutes was utilized. The flow rate was constant at 1.5mL/min.

Prep LC-MS: Preparative HPLC was performed on a Shimadzu Discovery VP®Preparative system fitted with a Luna 5 u C18(2) 100 A, AXIA packed,250×21.2 mm reverse-phase column at 22.4 degrees Celsius. The mobilephase consisted of a mixture of solvent 0.1% formic acid in water and0.1% formic acid in acetonitrile. A constant gradient from 95%aqueous/5% organic to 5% aqueous/95% organic mobile phase over thecourse of 25 minutes was utilized. The flow rate was constant at 20mL/min. Reactions carried out in a microwave were done so in a BiotageInitiator microwave unit.

Alternatively, the preparative HPLC was performed on a WatersPreparative system fitted with Column: XBridge Shield RP18 OBD Column,30*150 mm, Sum; The mobile phase consisted of a mixture of solvent Water(10 mmol/L NH₄HCO_(3+0.05)% NH3.H2O) and acetonitrile. A constantgradient from 95% aqueous/5% organic to 5% aqueous/95% organic mobilephase over the course of 11 minutes was utilized. The flow rate wasconstant at 60 mL/min. Reactions carried out in a microwave were done soin a Biotage Initiator microwave unit.

Silica gel chromatography: Silica gel chromatography was performed on aTeledyne Isco CombiFlash® Rf unit, a Biotage® Isolera Four unit, or aBiotage® Isolera Prime unit.

Proton NMR: ¹H NMR spectra were obtained with a Varian 400 MHz UnityInova 400 MHz NMR instrument (acquisition time=3.5 seconds with a 1second delay; 16 to 64 scans) or a Avance 400 MHz Unity Inova 400 MHzNMR instrument (acquisition time=3.99 seconds with a 1 second delay; 4to 64 scans) or a Avance 300 MHz Unity Inova 300 MHz NMR instrument(acquisition time=5.45 seconds with a 1 second delay; 4 to 64 scans).Unless otherwise indicated, all protons were reported in DMSO-d6 solventas parts-per million (ppm) with respect to residual DMSO (2.50 ppm).

SFC: Waters Preparative system.

Chiral-HPLC was performed on an Agilent 1260 Preparative system.

One of ordinary skill in the art will recognize that modifications ofthe gradient, column length, and flow rate are possible and that someconditions may be more suitable for compound characterization thanothers, depending on the chemical species being analyzed.

Generic Synthesis Schemes:

In certain embodiments optionally substituted bicyclic heteroaromatic,A1, where X═C or N, R═H, halo, optionally substituted alkyl, or —O-alkylis reacted with an optionally substituted azetidine, 1, where R1=H,alkyl and R2=optionally substituted methyl sulfone or sulfinimide usingstandard Buchwald coupling conditions to form optionally substitutedcondensation products, B1. The resulting species is further homologatedwith an optionally substituted pyrimidine or triazine where Y═C, N, O;n=0, 1, 2; and R3 and R4 are either or both H, halo, optionallysubstituted alklyl, O-alkyl, or N-Alkyl via a second Buchwald couplingto afford final products, C1.

SYNTHETIC EXAMPLES Example A1: Synthesis of3-(ethylsulfonylmethyl)azetidine Trifluoroacetic Acid Salt

Step I: Synthesis of tert-butyl3-(ethylthiomethyl)azetidine-1-carboxylate

Tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (2 g, 6.73 mmol, 1equiv.) and (ethylsulfanyl)sodium (1.12 g, 13.4 mmol, 2 equiv.) wasdissolved in mixture solvent (CH₃CN/H₂O=3:1, 20 mL). The resultingsolution was stirred at 60° C. for 18 h. The resulting solution wasconcentrated under vacuum. The residue was purified by chromatographywith DCM/MeOH (30/1). This resulted in 1.4 g (90%) of the title compoundas an off-white solid.

Analytical Data: LC-MS: (ES, m/z)=176 [M+1−56].

Step 2: Synthesis of tert-butyl3-(ethylsulfonylmethyl)azetidine-1-carboxylate

Tert-butyl 3-[(ethylsulfanyl)methyl]azetidine-1-carboxylate (1.4 g, 6.05mmol, 1 equiv.) was dissolved in mixture solvent (THF:EtOH=1:1, 10 mL),and then added pentapotassium sulfuric acid diperoxymonosulfate hydrogensulfate (Oxone, 11.1 g, 18.1 mmol, 3 equiv.) in 0.5 mL of water. Theresulting solution was stirred at 0° C. for 10 min, and then stirred atrt for 2 h. The resulting solution was concentrated under vacuum andpurified by chromatography with DCM/MeOH (20:1) to afford 1.3 g (81%) ofthe title compound as white solid.

Analytical Data: LC-MS: (ES, m/z)=286 [M+23].

Step 3: Synthesis of 3-(ethylsulfonylmethyl)azetidine TrifluoroaceticAcid Salt

Trifluoroacetic acid (3.36 g, 29.5 mmol) was added to a solution oftert-butyl 3-[(ethanesulfonyl)methyl]azetidine-1-carboxylate (1.3 g,4.93 mmol) in DCM (8 mL). The resulting solution was stirred at rt for 3h. The resulting solution was concentrated under vacuum and the residuewas washed with methyl tertiary butyl ether to afford 800 mg of thetitle compound as a white solid. Analytical Data: LC-MS: (ES, m/z)=164[M+1].

Example A2: Synthesis of 3-(isopropylsulfonylmethyl)azetidine

Step I: Synthesis of tert-butyl3-(isopropylthiomethyl)azetidine-1-carboxylate

Tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (200 mg, 673 μmol, 1equiv.) and (propan-2-ylsulfanyl)sodium (66.0 mg, 673 μmol, 1 equiv.)was dissolved in ACN (3 mL). The resulting solution was stirred at 80°C. for 16 h. The resulting solution was extracted with DCM, and then theorganic layers combined, dried over anhydrous sodium sulfate andconcentrated under vacuum. The resulted in 150 mg (90%) of the titlecompound.

Step 2: Synthesis of tert-butyl3-(isopropylsulfonylmethyl)azetidine-1-carboxylate

Tert-butyl 3-[(propan-2-ylsulfanyl)methyl]azetidine-1-carboxylate (140mg, 570 μmol, 1 equiv.) and pentapotassium sulfuric aciddiperoxymonosulfate hydrogen sulfate (525 mg, 855 μmol, 1.50 equiv.) wasdissolved in mixed solution (THF:EtOH:H₂O=1:1:1; 1 mL). The resultingsolution was stirred at room temperature for 2 h. The resulting solutionwas added sodium sulfite solution to end the reaction, then extractedwith EA. The organic layers was combined and concentrated under vacuum.This is resulted in 130 mg (82%) of the title compound as an off-white.

Analytical Data: LC-MS: (ES, m/z)=300 [M+23].

Step 3: Synthesis of 3-(isopropylsulfonylmethyl)azetidineTrifluoroacetic Acid Salt

Into a 8-mL tube was placed tert-butyl3-[(propane-2-sulfonyl)methyl]azetidine-1-carboxylate (120 mg, 432 μmol)in DCM (4 mL)/TFA (1 mL). The resulting solution was stirred at rt for 2h. The resulting solution was concentrated under vacuum. This resultedin 70 mg of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z)=178 [M+1].

Example A3: Synthesis of 3-((trifluoromethylsulfonyl)methyl)azetidine

Step 1: Synthesis of benzyl3-((trifluoromethylthio)methyl)azetidine-1-carboxylate

The mixture of benzyl 3-(hydroxymethyl)azetidine-1-carboxylate (100 mg,0.450 mmol, 1 equiv.), AgSCF₃ (420 mg, 1.8 mmol, 4.00 equiv.) and nBu₄NI(1725 mg, 5.4 mmol, 12 equiv.) in toluene (8 mL) was stirred for 12 h at80° C. The solids were filtered out. The resulting mixture wasconcentrated. The residue was applied onto a silica gel column withEA/PE (3:1). This resulted in 50 mg (36.4%) of the title compound as alight-yellow solid.

Analytical Data: LC-MS: (ES, m/z=306 [M+1].

Step 2: Synthesis of benzyl3-((trifluoromethylsulfonyl)methyl)azetidine-1-carboxylate

Oxone (330.5 mg, 1.97 mmol, 3 equiv.) was added the solution of benzyl3-[[(trifluoromethyl)sulfanyl]methyl]azetidine-1-carboxylate (200 mg,0.66 mmol, 1 equiv.) in THF (1 mL)/EtOH (1 mL)/H₂O (1 mL). The resultingsolution was stirred for 2 h at 60° C. The reaction was then quenched bythe addition of 1 mL of Na₂S₂O₃ and extracted with 3×5 mL of EA. Theresidue was applied onto a silica gel column with EA/PE (3:1). Thisresulted in 120 mg (54.5%) of the title compound as light-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=338 [M+1].

Step 3: Synthesis of 3-((trifluoromethylsulfonyl)methyl)azetidineHydrobromide

Benzyl 3-(trifluoromethanesulfonylmethyl)azetidine-1-carboxylate (50 mg,0.148 mmol, 1 equiv.) was added to ethanecarboperoxoyl bromide (30% inAcOH, 1 mL). The resulting solution was stirred for 3 h at rt. Theresulting mixture was concentrated and resulted in 20 mg (66.4%) of3-(trifluoromethanesulfonylmethyl)azetidine hydrobromide as alight-yellow solid. The crude product was used directly for next stepwithout further purification.

Analytical Data: LC-MS: (ES, m/z): =204 [M+1].

Example A4: Synthesis of(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine

Step 1: Synthesis of (2R,3S)-1-benzhydryl-2-methylazetidin-3-ylMethanesulfonate

(2R,3S)-1-benzhydryl-2-methylazetidin-3-ol (Pharmablock, 20 g, 78.9mmol) was dissolved in 300 mL DCM and TEA (9.55 g, 94.6 mmol) was addedand the reaction mixture cooled in an ice bath. Mesyl chloride (9.93 g,86.7 mmol) was added dropwise and allowed to stir, warming slowly to rtand stirred overnight. The mixture was diluted with DCM and washed withwater and the organic phase dried over sodium sulfate, filtered andevaporated to give 26 g (98%) of the title compound as a viscous yellowoil.

Analytical Data: LC-MS: (ES, m/z)=332 [M+1].

Step 2: Synthesis of (S)-methyl2-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate

(2R,3S)-1-benzhydryl-2-methylazetidin-3-yl methanesulfonate (26 g, 78.4mmol) and methyl 2-(methylsulfonyl)acetate (15.3 g, 101 mmol) weredissolved in 260 mL DMF and then NaH (3.75 g of 60% dispersion inmineral oil, 6.63 mmol) was added and stirred for ˜15 minutes, untilhydrogen evolution had ceased. The reaction mixture was heated to 80° C.overnight. The reaction was cooled and then diluted with ˜200 mL waterand extracted with EA and combined organics washed with water, brine anddried over sodium sulfate, filtered and evaporated to give the crudeproduct. The residue was purified by chromatography (0 to 7% MeOH/DCM).Pure fractions combined and evaporated to give 24 g (80%) of the titlecompound as a pale-yellow foam.

Step 3: Synthesis of(2R,3S)-1-benzhydryl-2-methyl-3-(methylsulfonylmethyl)azetidine

(S)-methyl-2-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate(24 g, 61.9 mmol) was dissolved in 240 mL DMA and lithium chloride (20.9g, 495 mmol) was added and the flask put into a preheated block that waskept at 150° C. LC/MS indicated the starting material was consumed after1.5 h. Cooled to room temperature and dilute with water, extracted withEA and the combined organics washed with water, brine and dried oversodium sulfate. Filtered and evaporated to give the crude product andfurther purified by chromatography (0 to 5% MeOH/DCM). Pure fractionswere combined and evaporated to give 19 g (93%) of the title compound asa pale-yellow foam.

Analytical Data: LC-MS: (ES, m/z)=330 [M+1].

Step 4: Synthesis of (2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine

To a solution of(2R,3S)-1-(diphenylmethyl)-3-(methanesulfonylmethyl)-2-methylazetidine(1 9 g, 57.3 mmol) in MeOH (270 mL) was added TFA (9 mL) and Pd(OH)₂(5.7 g), the reaction was stirred overnight at rt under H₂ atmosphere.The reaction mixture was filtered and evaporated to give the crude titlecompound (17 g) as a light-brown oil.

Analytical Data: LC-MS: (ES, m/z)=164 [M+1].

Example A5: Synthesis of 3-methyl-3-(methylsulfonylmethyl)azetidine

Step I: Synthesis of tert-butyl3-methyl-3-((methylsulfonyloxy)methyl)azetidine-1-carboxylate

Methanesulfonyl chloride (255 mg, 2.23 mmol) was added dropwise to TEA(301 mg, 2.98 mmol) and tert-butyl3-(hydroxymethyl)-3-methylazetidine-1-carboxylate (300 mg, 1.49 mmol) inDCM at 0° C. The mixture was stirred at rt for 4 h. The mixture wasdiluted with DCM, washed with brine. The organic layer was dried andconcentrated under vacuum to get 350 mg (95%) of the title compound as acolorless oil.

Analytical Data: LC-MS: (ES, m/z)=224 [M+1-56].

Step 2: Synthesis of tert-butyl3-methyl-3-(methylsulfonylmethyl)azetidine-1-carboxylate

Sodium methylsulfanide (175 mg, 2.50 mmol) was added to tert-butyl3-[(methanesulfonyloxy)methyl]-3-methylazetidine-1-carboxylate (350 mg,1.25 mmol) in ACN (30 mL) at rt. The resulting mixture was heated toreflux for 16 h. The mixture was diluted with DCM, washed with brine.The organic layer was concentrated under vacuum. The residue waspurified by a silica gel column with PE:EA=1:1. This resulted in 250 mg(75%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z)=176 [M+1−56].

Step 3: Synthesis of tert-butyl3-methyl-3-(methylsulfonylmethyl)azetidine-1-carboxylate

Oxone (362 mg, 2.16 mmol) was added to tert-butyl3-methyl-3-[(methylsulfanyl)methyl]azetidine-1-carboxylate (250 mg, 1.08mmol) in THF/H₂O/EtOH(5/5/5 mL) at rt. The resulting mixture was stirredat rt for 16 h. The mixture was extracted with EA, washed with brine.The organic layer was dried, concentrated under vacuum. The residue waspurified by a silica gel column with DCM:MeOH=20:1. This is resulted in200 mg (88%) of the title compound as a colorless.

Analytical Data: LC-MS: (ES, m/z)=208 [M+1−56].

Step 4: Synthesis of 3-methyl-3-(methylsulfonylmethyl)azetidine

TFA (5 mL) was added to tert-butyl3-(methanesulfonylmethyl)-3-methylazetidine-1-carboxylate (150 mg, 569μmol) in DCM (15 mL) at rt. The mixture was stirred at rt for 1 h. Themixture was concentrated under vacuum to afford 100 mg of the titlecompound as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=164 [M+1].

Example A6: Synthesis ofN-((azetidin-3-ylmethyl)(methyl)(oxo)-16-sulfaneylidene)benzamide

Step 1: Synthesis of Tert-butyl3-(methylthiomethyl)azetidine-1-carboxylate

A mixture of tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (5.05 g,17 mmol, 1 equiv.) and NaSMe (3.56 g, 25.5 mmol, 1.50 equiv.) in MeCN(30 mL) and H₂O (10 mL) was heated to 60° C. for 18 h. After coolingdown to rt, the mixture was concentrated, the residue was diluted withEA. The organic solution was washed with water, dried over Na₂SO₄. Thissolution was concentrated to afford the title compound (3.69 g, quant.)as a light-yellow oil.

Step 2: Synthesis of tert-butyl3-(methylsulfinylmethyl)azetidine-1-carboxylate

A solution of tert-butyl3-[(methylsulfanyl)methyl]azetidine-1-carboxylate (3.69 g, 17 mmol, 1equiv.) in DCM (50 mL) was added mCPBA (2.92 g, 17 mmol, 1 equiv.)portionwise at 0° C. The reaction was carried on at 0° C. for 2 h beforequenching by adding sat. NaHCO₃ (200 mL). The mixture was extracted withDCM. The organic layer was combined and concentrated, the residue waspurified by silica gel column chromatography (DCM/MeOH=15:1) to affordthe title compound (2.7 g, 68.2%) as a light-yellow syrup.

Step 3: Synthesis of tert-butyl3-(S-methylsulfonimidoylmethyl)azetidine-1-carboxylate

A mixture of tert-butyl 3-(methanesulfinylmethyl)azetidine-1-carboxylate(2.68 g, 11.5 mmol, 1 equiv.), Ammonium acetate (4.41 g, 57.4 mmol, 5.00equiv.) and PhI(OAc)₂ (5.53 mg, 17.2 mmol, 1.50 equiv.) in MeCN (60 mL)was stirred at 35° C. for 18 h. The mixture was filtered and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH=15:1) to afford the title compound (1.5 g,52.63%) as a light-yellow syrup.

Analytical Data: LC-MS: (ES, m/z)=249 [M+1].

Step 4: Synthesis of tert-butyl3-((N-benzoyl-S-methylsulfonimidoyl)methyl)azetidine-1-carboxylate

A mixture of tert-butyl3-{[imino(methyl)-oxo-λ⁶-sulfanyl]methyl}azetidine-1-carboxylate (372mg, 1.50 mmol, 1 equiv.) and DMAP (366 mg, 3 mmol, 2 equiv.) in DCM (6mL) was added BzCl (281 mg, 2 mmol, 1.33 equiv.) at 0° C. The reactionwas carried on at rt for 3 h and concentrated. The residue was purifiedby silica gel column chromatography (DCM/MeOH=20:1) to afford the titlecompound (440 mg, 83.3%) as a yellow syrup.

Analytical Data: LC-MS: (ES, m/z)=375 [M+23].

Step 5: Synthesis ofN-((azetidin-3-ylmethyl)(methyl)(oxo)-16-sulfaneylidene)benzamide

Tert-butyl3-((N-benzoyl-S-methylsulfonimidoyl)methyl)azetidine-1-carboxylate (440mg, 1.25 mmol, 1 equiv.) in TFA (1 mL) and DCM (3 mL) was stirred at rtfor 4 h. The mixture was concentrated to afford the title compound (315mg, quant.) trifluoroacetic acid salt as a yellow syrup.

Example A7: Synthesis of(2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidine

Step 1: Synthesis of methyl 2-(ethylthio)acetate

The solution of methyl 2-sulfanylacetate (20 g, 188 mmol), iodoethane(87.9 g, 564 mmol) and K₂CO₃ (39.5 g, 282 mmol) in THF (300 mL) wasreflux for 5 h. Water was added and the reaction mixture was extractedwith EA. The organic layer was concentrated under vacuum to give thetitle compound (20 g) as a light-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=157 [M+23].

Step 2: Synthesis of methyl 2-(ethylsulfonyl)acetate

m-CPBA (76.7 g, 446 mmol) was added to a solution of methyl2-(ethylsulfanyl)acetate (20 g, 149 mmol) in DCM (500 mL) at 0° C. andthe reaction was stirred at rt overnight. The reaction mixture waswashed with water and concentrated under vacuum. The residue was appliedonto a silica gel column with EA/PE (1:3) to give the title compound(13.5 g) as a light-yellow oil.

Step 3: Synthesis of methyl2-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-2-(ethylsulfonyl)acetate

(2R,3S)-1-benzhydryl-2-methylazetidin-3-yl methanesulfonate (Step 1,Example A4 13 g 39.2 mmol) and methyl 2-(ethanesulfonyl)acetate weredissolved in 130 mL DMF, and then NaH (1.12 g of 60% dispersion inmineral oil, 47.0 mmol) was added and stirred for ˜15 minutes, untilhydrogen evolution had ceased. The reaction mixture was heated to 80° C.overnight. The reaction was cooled and then diluted with water andextracted with EA and combined organics washed with water, brine anddried over sodium sulfate. Filter and evaporate to give the crudeproduct. The crude product was purified by chromatography (0 to 7%MeOH/DCM to give 8 g of the title compound as a pale-yellow foam.

Analytical Data: LC-MS: (ES, m/z)=402 [M+1].

Step 4: Synthesis of(2R,3S)-1-benzhydryl-3-(ethylsulfonylmethyl)-2-methylazetidine

To a solution of methyl2-[(2R,3S)-1-(diphenylmethyl)-2-methylazetidin-3-yl]-2-(ethanesulfonyl)acetate(8 g, 19.9 mmol) in DMA (150 mL) was added chlorolithium (6.74 g, 159mmol) and heated to 150° C. for 1.5 h. Cool to rt and dilute with 150 mLwater and extract (×3) with EA and the combined organics washed withwater (×3), brine and dried over sodium sulfate. Filter and evaporate togive the crude product, which was purified by chromatography (0 to 5%MeOH/DCM) to give 6 g of the title compound as a pale-yellow foam.

Analytical Data: LC-MS: (ES, m/z)=344 [M+1].

Step 5: Synthesis of (2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidine

To a solution of methyl2-[(2R,3S)-1-(diphenylmethyl)-2-methylazetidin-3-yl]-2-(ethanesulfonyl)acetate(6 g, 14.9 mmol) in MeOH (270 mL)/TFA (30 mL) was stirred at rtovernight under H₂ atmosphere. The reaction was filter and concentratedunder vacuum to give the title compound 3.8 g (trifluoroacetic acidsalt) as light-brown oil.

Analytical Data: LC-MS: (ES, m/z)=178 [M+1].

Example A8: Synthesis ofrac-N-(methyl(((trans)-2-methylazetidin-3-yl)methyl)(oxo)-16-sulfaneylidene)benzamide

Step 1: Synthesis of rac-tert-butyl(trans)-3-(hydroxymethyl)-2-methylazetidine-1-carboxylate

A solution ofrac-(trans)-1-[(tert-butoxy)carbonyl]-2-methylazetidine-3-carboxylicacid (1.50 g, 7 mmol, 1 equiv.) in THF (20 mL) was added BH₃ (21.0 mL,21.0 mmol, 3 equiv., 1M in THF) at 0° C. The reaction was carried on atrt for 18 h before quenching with 1N HCl (10 mL). The mixture wasneutralized with 10% Na₂CO₃. The mixture was extracted with EA (30mL*3). The organic layer was combined and concentrated. The residue waspurified by silica gel column chromatography (DCM/EA=1:1) to afford thetitle compound (1.2 g, 85.7%) as a colourless syrup.

Analytical Data: 1H-NMR (300 MHz, CD₃Cl) δ ppm 4.09-3.99 (m, 1H), 3.91(t, 1H, J=8.5 Hz), 3.76 (dd, 2H, J=6.5, 5.2 Hz), 3.60 (dd, 1H, J=8.6,6.0 Hz), 2.33-2.21 (m, 1H), 1.54 (t, 1H, J=5.3 Hz), 1.46 (s, 9H), 1.41(d, 3H, J=6.3 Hz)

Step 2: Synthesis of rac-(trans)-tert-butyl2-methyl-3-(methylthiomethyl)azetidine-1-carboxylate

A solution of rac-tert-butyl(trans)-3-(hydroxymethyl)-2-methylazetidine-1-carboxylate (1.20 g, 6mmol, 1 equiv.) in DCM (35 mL) was added TEA (1.21 g, 12.0 mmol, 2equiv.), followed by MsCl (889 mg, 7.80 mmol, 1.3 equiv.) at 0° C. Thereaction was carried on at 0° C. for 1 h before quenching with sat.NaHCO₃ (50 mL). The mixture was extracted with DCM (30 mL*3). Theorganic layer was combined and concentrated. The residue was dissolvedin MeCN (12 mL) and H₂O (3 mL). NaSMe (840 mg, 12.0 mmol, 2 equiv.) wasadded. The reaction was carried on at 60° C. for 18 h. After coolingdown to rt, EA (100 mL) was added. The mixture was washed with water (50mL) and concentrated. The residue was purified by silica gel columnchromatography (PE/EA=4:1) to afford the title compound (1.38 g, quant.)as a yellow oil.

Analytical Data: 1H-NMR (300 MHz, CD₃Cl) δ ppm 3.96 (dd, 2H, J=9.8, 7.0Hz), 3.51 (dd, 1H, J=8.7, 6.1 Hz), 2.69 (d, 2H, J=7.8 Hz), 2.34-2.23 (m,1H), 2.12 (s, 3H), 1.46 (s, 9H), 1.42 (d, 3H, J=6.2 Hz)

Step 3: Synthesis of rac-(trans)-tert-butyl2-methyl-3-(methylsulfinylmethyl)azetidine-1-carboxylate

A solution of rac-tert-butyl(trans)-2-methyl-3-[(methylsulfanyl)methyl]azetidine-1-carboxylate (1.38g, 6 mmol, 1 equiv.) in DCM (30 mL) was added mCPBA (1.08 g, 6.30 mmol,1.05 equiv.) portionwise at 0° C. for 2 h before quenching with sat.NaHCO₃ (50 mL). The mixture was extracted with DCM (30 mL*3). Theorganic layer was combined and concentrated. The residue was purified bysilica gel column chromatography (DCM/MeOH=15:1) to afford the titlecompound (1.2 g, 81.1%) as a light-yellow oil.

Analytical Data: 1H-NMR (300 MHz, CD₃Cl) δ ppm 4.15-4.02 (m, 2H), 3.66(td, 1H, J=9.0, 6.2 Hz), 3.11-2.79 (m, 2H), 2.74-2.65 (m, 1H), 2.61 (d,3H, J=3.9 Hz), 1.51-1.40 (m, 12H)

Step 4: Synthesis of rac-(2R,3S)-tert-butyl2-methyl-3-(S-methylsulfonimidoylmethyl)azetidine-1-carboxylate

A mixture of rac-tert-butyl(trans)-3-(methanesulfinylmethyl)-2-methylazetidine-1-carboxylate (1.23g, 5 mmol, 1 equiv.), PhI(OAc)₂ (2.41 g, 7.50 mmol, 1.5 equiv.) andammonium acetate (2.31 g, 30.0 mmol, 6 equiv.) in ACN (30 mL) wasstirred at 35° C. for 18 h. After cooling down to rt, the mixture wasconcentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH=15:1) to afford the title compound (600 mg,45.8%) as a light-yellow syrup.

Analytical Data: LC-MS: (ES, m/z)=263 [M+1].

Step 5: Synthesis of rac-tert-butyl(trans)-3-((N-benzoyl-S-methylsulfonimidoyl)methyl)-2-methylazetidine-1-carboxylate

A mixture of rac-tert-butyl(trans)-3-{[imino(methyl)oxo-λ⁶-sulfanyl]methyl}-2-methylazetidine-1-carboxylate(393 mg, 1.5 mmol, 1 equiv.) and DMAP (292 mg, 2.40 mmol, 1.6 equiv.) inDCM (5 mL) was added benzoyl chloride (274 mg, 1.95 mmol, 1.3 equiv.) at0° C. The reaction was carried on at 0° C. for 2 h before quenching withsat. NaHCO₃ (20 mL). The mixture was extracted with DCM (20 mL*3). Theorganic layer was combined and concentrated. The residue was purified bysilica gel column chromatography (DCM/EA=1:1) to afford the titlecompound (400 mg, 72.9%) as a colourless syrup.

Analytical Data: LC-MS: (ES, m/z)=367 [M+1].

Step 5: Synthesis ofrac-N-(methyl(((trans)-2-methylazetidin-3-yl)methyl)(oxo)-16-sulfaneylidene)benzamide

A solution of rac-(trans)-tert-butyl3-((N-benzoyl-S-methylsulfonimidoyl)methyl)-2-methylazetidine-1-carboxylate(732 mg, 2 mmol, 1 equiv.) in TFA (2 mL) and DCM (6 mL) was stirred atrt. for 3 h. The mixture was concentrated to afford the title compound(370 mg, 69.6%) as a colorless syrup.

Analytical Data: LC-MS: (ES, m/z)=267 [M+1].

Example B1: Synthesis of(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol and(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol and(3R,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol and(3S,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol

Step 1: Synthesis of tert-butyl3-methyl-4-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate

Trimethylsilyl trifluoromethanesulfonate (12.50 g, 56.25 mmol, 1.20equiv.) was added drop wise to a pre-cooled solution oftert-butyl3-methyl-4-oxopiperidine-1-carboxylate (10 g, 46.88 mmol, 1equiv.) and TEA (11.38 g, 112.5 mmol, 2.40 equiv.) in toluene (100 mL)at 0° C. The resulting mixture was stirred for 4 h at 0° C. The solutionwas quenched with water (50 mL) and extracted twice with EA. The organiclayers were combined, washed with brine, dried over anhydrous sodiumsulfate and concentrated in vacuum to afford the title compound thetitle compound (10.5 g, 78.5%) as yellow oil.

Analytical Data: 1H-NMR (400 MHz, 6d-DMSO) δ ppm 3.68-3.66 (m, 2H), 3.43(t, 2H, J=5.8 Hz), 2.05 (tq, 2H, J=6.0, 2.0 Hz), 1.53-1.47 (m, 3H), 1.41(s, 9H), 0.15 (s, 9H).

Step 2: Synthesis of tert-butyl3-fluoro-3-methyl-4-oxopiperidine-1-carboxylate

A mixture of tert-butyl5-methyl-4-[(trimethylsilyl)oxy]-1,2,3,6-tetrahydropyridine-1-carboxylate(10 g, 35.0 mmol, 1 equiv.) and SelectFluor (13.6 g, 38.5 mmol, 1.10equiv.) in acetonitrile (100 mL) and stirred for 1 h at 0° C. Thesolution was diluted with water (100 mL) and extracted with EA. Theorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuum. This resulted in 8 g(98.8%) of the title compound as light-yellow oil.

Step 3: Synthesis of tert-butyl3-fluoro-4-hydroxy-3-methylpiperidine-1-carboxylate

The mixture of tert-butyl3-fluoro-3-methyl-4-oxopiperidine-1-carboxylate (7 g, 30.2 mmol, 1equiv.) and NaBH₄ (1.37 g, 36.2 mmol, 1.12 equiv.) in methanol (70 mL)was stirred for 3 h at rt. The solution was extracted with EA. Theorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuum. This resulted in the crudecompound 7 g (99.4%) of the title compound light-yellow oil.

Step 4: Synthesis of 3-fluoro-3-methylpiperidin-4-ol Hydrochloride

To a reaction vessel was added tert-butyl3-fluoro-4-hydroxy-3-methylpiperidine-1-carboxylate (7 g, 30.0 mmol),DCM (70 mL) and hydrochloric (4 M in dioxane, 50 mL). The resultingmixture was stirred at rt for 3 h. The reaction precipitate wascollected by filtration to afford the title compound the title compound(4.5 g) as a white solid.

Step 5: Synthesis of1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol

The mixture of 2-chloropyrimidin-4-amine (2.7 g, 20.8 mmol, 1 equiv.),3-fluoro-3-methylpiperidin-4-ol hydrochloride (3.86 g, 22.8 mmol, 1.10equiv.) and TEA (6.30 g, 62.4 mmol, 3 equiv.) in isopropyl alcohol (45mL) stirred for 5 h at 130° C. in a sealed vial. The reaction mixturewas cooled to rt. The solids were filtered out. The filtrate wasconcentrated under vacuum to give the crude compound the title compound(6 g) as a yellow oil.

The crude product1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol was purifiedby HP-FLASH with the following conditions (Column: XBridge Prep OBD C18Column 30×150 mm 5 um; Mobile Phase A: Water (3 MMOL/L NH₄HCO₃), MobilePhase B: ACN; Flow rate: 100 mL/min; Gradient: 10% B to 30% B in 35 min;254/220 nm; Rt: 21.12 min). The fractions containing the desiredcompound were evaporated to dryness to afford cis racemate (1.3 g,26.1%) as a white solid and trans racemate (500 mg, 10.0%) as a whitesolid.

The cis racemate(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol wasseparated by Prep-Chiral-SFC-HPLC with the following conditions (Column:Phenomenex Lux 5 u Cellulose-3, 5*25 cm, 5 um; Mobile Phase A: CO₂: 50,Mobile Phase B: MEOH (0.1% DEA): 50; Flow rate: 170 mL/min; 220 nm). Thefractions containing the desired compound were evaporated to dryness toafford (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol(Stereochemistry assigned by xray crystallography of Compound 55; 500mg, peak 1) as a white solid and(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (500mg, peak 2) as a white solid.

Analytical Data: LC-MS: (ES, m/z)=227 [M+1]; 1H-NMR (400 MHz, 6d-DMSO) δppm 7.71 (d, 1H, J=5.6 Hz), 6.37 (s, 2H), 5.69 (d, 1H, J=5.6 Hz), 4.93(d, 1H, J=6.5 Hz), 4.66 (ddd, 1H, J=14.1, 9.1, 2.2 Hz), 4.60-4.50 (m,1H), 3.44 (ddt, 1H, J=24.8, 11.0, 5.6 Hz), 3.02-2.78 (m, 2H), 1.69-1.53(m, 2H), 1.31 (d, 3H, J=21.2 Hz).

The trans racemate was separated by Prep-Chiral-SFC with the followingconditions (Column: CHIRALPAK AD-H-TC001 SFC, 2*25 cm, 5 um; MobilePhase A: CO₂: 70, Mobile Phase B: MeOH-Preparative: 30; Flow rate: 40mL/min; 220 nm) The fractions containing the desired compound wereevaporated to dryness to afford(3R,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or(3S,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (180mg) as a white solid (peak 1) and(3S,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or(3R,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (190mg) as a white solid (peak 2).

Analytical Data: LC-MS: (ES, m/z)=227 [M+1]; 1H-NMR (300 MHz, 6d-DMSO) δppm 7.72 (d, 1H J=5.7 Hz), 6.40 (s, 2H), 5.70 (d, 1H, J=5.6 Hz), 5.24(d, 1H, J=4.5 Hz), 3.83-3.56 (m, 5H), 1.78 (ddt, 1H, J=12.9, 10.0, 4.7Hz), 1.48-1.36 (m, 1H), 1.24 (d, 3H, J=22.5 Hz).

Example B2: Synthesis of(S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amineand(R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine

Step 1: Synthesis of tert-butyl5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane-7-carboxylate

Tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (2 g, 8.50 mmol, 1equiv.), trimethylsulfoxonium iodide (5.61 g, 25.5 mmo, 3 equiv.) andt-BuOK (2.85 g, 25.5 mmol, 3 equiv.) was dissolved/suspended in t-BuOH.The mixture was stirred at 50° C. for 2 days. The reaction mixture wasadded water and extracted with EA. The organic layers and concentratedunder vacuum. This resulted in 2 g (89%) of the title compound.

Step 2: Synthesis of 5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane

TFA (3 mL) was added to tert-butyl5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane-7-carboxylate (2 g, 7.59 mmol)in DCM (10 mL). The reaction was stirred at rt for 2 h. The mixture wasconcentrated under vacuum to afford the title compound 2.1 g as thetrifluoroacetic acid salt. The crude product was used directly for nextstep.

Analytical Data: LC-MS: (ES, m/z)=164 [M+1].

Step 3: Synthesis of(S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amineand(R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine

TEA (12.3 g, 122 mmol, 2 equiv.) was added to5,5-difluoro-1-oxa-7-azaspiro[3.5]nonane (10 g, 61.2 mmol, 1 equiv.) and2-chloropyrimidin-4-amine (8.41 g, 61.2 mmol, equiv.) in DMSO (100 mL).The reaction was stirred at 100° C. for 2 h. The mixture was added waterand extracted with EA. The organic layers and washed with brine, driedand concentrated. The residue was purified by FLASH (5% MeOH in DCM) togive the title compound (2.1 g).

2.1 g of the product was separated by Prep-SFC-HPLC with the followingconditions (Column: Column: CHIRALART Amylose-SA, 2*25 cm, 5 um; MobilePhase A: CO₂, Mobile Phase B: EtOH; Flow rate: 40 mL/min; Gradient: 35%B; 254 nm, fractions containing the desired compound were evaporated todryness to afford 800 mg of peak 1:(S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine or(R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amineand peak 2: 805 mg of(R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine or(S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine.

peak 1:(S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine or(R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine

Analytical Data: LC-MS: (ES, m/z)=257 [M+1]; 1H-NMR (300 MHz, 6d-DMSO) δppm 7.74 (d, 1H, J=5.6 Hz), 6.52 (s, 2H), 5.77 (d, 1H, J=5.7 Hz), 4.46(t, 2H, J=7.8 Hz), 4.23 (td, 1H, J=14.1, 7.2 Hz), 3.93-3.74 (m, 2H),3.53 (ddd, 1H, J=13.2, 8.9, 3.5 Hz), 2.74 (dt, 1H, J=11.4, 7.5 Hz),2.50-2.39 (m, 1H), 2.10-1.97 (m, 1H), 1.90 (ddt, 1H, J=13.4, 8.9, 4.3Hz).

peak 2:(R)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine or(S)-2-(5,5-difluoro-1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine

Analytical Data: LC-MS: (ES, m/z)=257 [M+1]; 1H-NMR (300 MHz, 6d-DMSO) δppm 7.75 (d, 1H, J=5.7 Hz), 6.52 (s, 2H), 5.77 (d, 1H, J=5.6 Hz), 4.46(t, 2H, J=7.8 Hz), 4.23 (td, 1H, J=14.2, 7.2 Hz), 3.93-3.74 (m, 2H),3.53 (ddd, 1H, J=13.1, 8.8, 3.5 Hz), 2.74 (dt, 1H, J=11.4, 7.5 Hz),2.50-2.41 (m, 1H), 2.10-1.97 (m, 1H), 1.91 (ddt, 1H, J=13.4, 8.8, 4.3Hz).

Example B3: Synthesis of 2-(4-methylpiperazin-1-yl)pyrimidin-4-amine

The mixture of 2-chloropyrimidin-4-amine (300 mg, 2.31 mmol, 1 equiv.),1-methylpiperazine (231 mg, 2.31 mmol, 1 equiv.) and TEA (466 mg, 4.62mmol, 2 equiv.) in IPA (3 mL) was heated to 100° C. for 1.5 h. LCMSshowed the reaction was complete. The mixture was diluted with water andextracted with EA. The organic phase was dried, concentrated andpurified by FLASH (DCM:MeOH=5%). This is resulted in the title compound,270 mg (60%) as yellow solid.

Analytical Data: LC-MS: (ES, m/z)=194 [M+1].

Example B4: Synthesis of 2-(4-methoxypiperidin-1-yl)pyrimidin-4-amine

The mixture of 4-methoxypiperidine (1.15 g, 10 mmol, 1.0 equiv.),2-chloropyrimidin-4-amine (1.3 g, 10 mmol, 1.0 equiv.) and TEA (2.0 g,20 mmol, 2.0 equiv.) in IPA (15 mL) was stirred overnight at 100° C. Themixture was concentrated and residue was purified by Combi Flash (5%MeOH in DCM) to afford the title compound, 1.12 g (53%) as pale-yellowsolid.

Analytical Data: LC-MS: (ES, m/z)=209 [M+1].

Example B5: Synthesis of 2-morpholinopyrimidin-4-amine

The mixture of 2-chloropyrimidin-4-amine (296 mg, 2.3 mmol, 1 equiv),morpholine (200 mg, 2.3 mmol, 1 equiv.) and TEA (460 mg, 4.6 mmol, 2.0equiv.) in IPA (5 mL) was stirred for 5 h at 100° C. The mixture wascooled to rt and concentrated. The reside was purified by Prep-TLC toafford the title compound, 360 mg (87%) as yellow solid.

Analytical Data: LC-MS: (ES, m/z)=181 [M+1].

Example B6: Synthesis ofrac-2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-amine

The mixture of 1-oxa-7-azaspiro[3.5]nonane (1.27 g, 10 mmol, 1 equiv.),DIPEA (2.6 g, 20 mmol, 2 equiv.) and 2-chloropyrimidin-4-amine (1.29 g,10 mmol, 10.00 equiv.) in DMSO (12 mL) was stirred overnight at 120° C.The mixture of cooled to rt and diluted with water. The suspension wasextracted with EA. The organic layers was washed with brine, dried andconcentrated. The residue was purified by Prep-TLC to afford the titlecompound, 1.3 g (59%) as pale-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=221 [M+1].

Example B7: Synthesis of2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrimidin-4-amine

To a solution of commercially available(3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole (841 mg, 6.49 mmol, 1 equiv.)in IPA were added commercially available hexahydro-1H-furo[3,4-c]pyrrole(970 mg, 8.57 mmol, 1.32 equiv.) and TEA (1.30 g, 12.9 mmol, 2 equiv.)and heated to 100° C. and stirred overnight. LCMS showed the reactionwas complete. The mixture was added water and extracted with EA. Theorganic phase was concentrated and purified by FLASH (5% MeOH in DCM).This is obtained the title compound, 500 mg (37%) as pale-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=207 [M+1].

Example B8: Synthesis of2-((3R,4S)-3,4-difluoropyrrolidin-1-yl)pyrimidin-4-amine

In a 20 mL sealed tube, 2-chloropyrimidin-4-amine (600 mg, 4.63 mmol, 1equiv.), (3R,4S)-3,4-difluoropyrrolidine (495 mg, 4.63 mmol, 1 equiv.),TEA (1.39 g, 13.8 mmol, 3 equiv.) in IPA (10 mL) were added undernitrogen and warmed to 100° C. for 12 h. The reaction mixture wasfiltered, evaporated to afford the title compound, 800 mg (86%) as ayellow solid.

Analytical Data: LC-MS: (ES, m/z)=201 [M+1].

Example B9: Synthesis of1-(4-aminopyrimidin-2-yl)-4-methylpiperidin-4-ol

The mixture of 4-methylpiperidin-4-ol (230 mg, 2 mmol, 1 equiv.),2-chloropyrimidin-4-amine (258 mg, 2 mmol, 1 equiv.) and TEA (300 mg, 3mmol, 1.5 equiv.) in IPA (5 mL) was stirred overnight at rt. The solventwas removed under vacuum. The residue was purified by Prep-TLC (6% MeOHin DCM) to afford the title compound, 210 mg (50%).

Analytical Data: LC-MS: (ES, m/z)=209 [M+1].

Example B10: Synthesis of(3S,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol and(3R,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol

Step 1: Synthesis ofcis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol

The mixture of cis-4-methoxypiperidin-3-ol (1.7 g, 13 mmol, 1 equiv.),2-chloropyrimidin-4-amine (1.7 g, 13 mmol, 1 equiv.) and TEA (2.6 g, 26mmol, 2.0 equiv.) in IPA (15 mL) was stirred overnight at 100° C. Themixture was concentrated and the residue was purified by FLASH (5% MeOHin DCM) to afford the title compound, 2.4 g (82.7%) as yellow solid.

Analytical Data: LC-MS: (ES, m/z)=225 [M+1].

Step 2: Synthesis of(3S,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol and(3R,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol

2.4 of cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol 2.4 g wasseparated by Chiral-SFC by following conditions: Column name, CHIRALPAKIA (4.6*150 mm, 5 um); solvent, CO₂/10% MEOH (0.1% DEA); Flow rate, 4mL/min; The fractions containing the desired compound were evaporated todryness to afford peak 1:(3S,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol or(3R,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol (900 mg) andpeak 2: (3R,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol or (3S,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol (890 mg).

Example B11: Synthesis of(4R,5S)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-oland(4S,5R)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol

Step 1: Synthesis of cis-5-fluoro-3,3-dimethylpiperidin-4-ol

Cis-tert-butyl 5-fluoro-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate(4.7 g, 19.0 mmol) was added to a solution of HCl in 1,4-dioxane (30mL), the resulting mixture was stirred at rt for 16 h. The solvent wasremoved under reduced pressure to afford the title compound as thehydrochloride salt, 3.6 gas a white solid.

Step 2: Synthesis ofcis-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol

TEA (3.83 g, 38.0 mmol) was added to a mixture ofcis-5-fluoro-3,3-dimethylpiperidin-4-ol (3.6 g, 19.0 mmol) and2-chloropyrimidin-4-amine (2.46 g, 19.0 mmol) in iPrOH (10 mL), theresulting mixture was stirred at 100° C. for 3 h. The solid was filteredout, the filtrate was concentrated under reduced pressure. The crudeproduct was purified by preparative HPLC: Column: XBridge Prep OBD C18Column 30×150 mm 5 um; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to32% B in 8 min; 254/220 nm; Rt: 6.92 min; Fractions containing thedesired compound were evaporated to dryness to afford the title compound(1.8 g, 39.4%) as a white solid.

Analytical Data: LC-MS: (ES, m/z)=241 [M+1].

Step 3: Synthesis of(4R,5S)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-oland(4S,5R)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol

The 1.8 g of cis racemate was separated by preparative chiral-HPLConColumn: EnantioPak-A1-5(02), 5*25 cm, 5 um; Mobile Phase A: CO₂:60,Mobile Phase B: EtOH 0.1% DEA; Flow rate: 2 mL/min; 220 nm. Thefractions containing the desired compound were evaporated to dryness toafford peak 1:(4R,5S)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol or(4S,5R)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol(776 mg, 43.3%) as a white solid, and peak 2:(4S,5R)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol or(4R,5S)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol(700 mg, 39.1%) as a white solid.

(4R,5S)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol or(4S,5R)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethylpiperidin-4-ol

Analytical Data: LC-MS: (ES, m/z)=241 [M+1]; 1H-NMR (300 MHz, 6d-DMSO) δppm 7.69 (d, 1H, J=5.7 Hz), 6.36 (s, 2H), 5.67 (d, 1H, J=5.6 Hz), 5.00(d, 1H, J=5.4 Hz), 4.75-4.47 (m, 1H), 4.09-3.93 (m, 1H), 3.86-3.67 (m,1H), 3.62 (d, 1H, J=12.9 Hz), 3.37 (ddd, 1H, J=22.0, 5.5, 2.9 Hz),3.31-3.18 (m, 1H), 0.95-0.78 (m, 6H).

Example B12: Synthesis of(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol and(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol

Step 1: Synthesis of rac-cis-tert-butyl3-fluoro-4-hydroxy-4-methylpiperidine-1-carboxylate

MeMgBr (9.2 mL, 27.6 mmol) was added to a solution of tert-butyl3-fluoro-4-oxopiperidine-1-carboxylate (5 g, 2.3 mmol) in THF (50 mL) at−78° C. The mixture was stirred overnight at rt. The reaction mixturewas carefully diluted with sat. NH₄Cl (aq), then extracted with EA andwashed with brine. The organic layer was dried over Na₂SO₄, filtered,evaporated to afford the title compound 4.8 g (crude) as a yellow solid.

Analytical Data:LC-MS: (ES, m/z)=178 [M+1−56].

Step 2: Synthesis of rac-cis-3-fluoro-4-methylpiperidin-4-ol

Tert-butyl 3-fluoro-4-hydroxy-4-methylpiperidine-1-carboxylate (4.8 g,20 mmol) in HCl/dioxane (50 mL) was stirred at rt for 4 h. The reactionmixture was evaporated to afford 3-fluoro-4-methylpiperidin-4-ol 3 g(crude) as a yellow solid. The crude product was used directly for nextstep.

Analytical Data: LC-MS: (ES, m/z)=134 [M+1].

Step 3: Synthesis ofrac-cis-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol

The mixture of 2-chloropyrimidin-4-amine (1.5 g, 11.5 mmol),3-fluoro-4-methylpiperidin-4-ol (3 g, crude) and DIPEA (11.9 g, 92.3mmol) in DMSO (40 mL) was stirred overnight at 120° C. The reactionmixture was diluted with water, extracted with EA and washed with brine.The organic layer was dried over Na₂SO₄, filtered, evaporated, purifiedby column chromatography (PE:EA=1:1) to afford the title compound (1.3g) as a light-yellow solid.

Analytical Data:LC-MS: (ES, m/z)=227 [M+1].

Step 4: Synthesis of(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol and(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol

Rac-cis 1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol wasseparated by preparative SFC with following conditions: Column: CHIRALCellulose-SJ (4.6*150 mm, 5 um); Mobile Phase: CO₂/MeOH (0.1% DEA); FlowRate: 4 g/min); to afford peak 1:(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (450mg, Stereochemistry assigned by xray crystallography of Compound 117) asa white solid and peak 2:(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (470mg) as a white solid.

peak 1: (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol

Analytical Data: 1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.73 (d, 1H J=5.6 Hz),6.40 (s, 2H), 5.72 (d, 1H, J=5.6 Hz), 4.71 (s, 1H), 4.39-3.92 (m, 3H),3.38 (dddd, 2H, J=40.5, 13.6, 10.3, 4.6 Hz), 1.62 (q, 1H, J=6.2 Hz),1.42 (td, 1H, J=13.6, 12.0, 4.3 Hz), 1.20 (s, 3H).

peak 2: (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol

Analytical Data: 1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.73 (d, 1H, J=5.6 Hz),6.40 (s, 2H), 5.72 (d, 1H, J=5.6 Hz), 4.71 (s, 1H), 4.36-4.07 (m, 2H),4.07-3.95 (m, 1H), 3.44 (ddd, 1H, J=13.2, 9.4, 4.8 Hz), 3.31 (ddd, 1H,J=13.4, 8.3, 3.2 Hz), 1.61 (ddt, 1H, J=14.1, 7.2, 3.9 Hz), 1.41 (ddd,1H, J=13.9, 10.3, 4.4 Hz), 1.20 (s, 3H).

Example B13: Synthesis of(S)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol and(R)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol

Step 1: Synthesis of1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol

The mixture of 3,3-difluoro-4-methylpiperidin-4-ol (300 mg, 2.0 mmol),2-chloropyrimidin-4-amine (260 mg, 2.0 mmol) and TEA (300 mg, 3.0 mmol)in DMSO (2 mL) was stirred overnight at 120° C. Water was added and themixture was extracted with EA. The organic phase was washed with brine,dried and purified by FLASH (5% MeOH in DCM) to give 320 mg (65%) of thetitle compound as white solid.

Analytical Data: LC-MS: (ES, m/z)=245 [M+1].

Step 2: Synthesis of(S)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol and(R)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol

320 mg of 1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-olwas separated by Prep-chiral-SFC with following conditions: Column name:CHIRALPAK AD-3 3*100 m m, 3 um; Co-Solvent: MeOH (0.1% DEA); Gradient (B%): 10% to 50% in 4.0 min, hold 2.0 min at 50%; Back Pressure (psi):1500.000; Flow: 2 mL/min; to give 145 mg of peak 1:(S)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol or(R)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol andpeak 2: 150 mg of(R)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol or(S)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol. Bothare pale-yellow solid.

Analytical Data: 1H-NMR (300 MHz, 6d-DMSO) δ ppm 7.74 (d, 1H, J=5.6 Hz),6.45 (s, 2H), 5.74 (d, 1H, J=5.7 Hz), 5.41 (s, 1H), 4.58 (dt, 1H,J=13.4, 9.4 Hz), 4.29 (d, 1H, J=13.3 Hz), 3.59-3.38 (m, 1H), 3.23 (ddd,1H, J=13.8, 9.6, 4.7 Hz), 1.62 (q, 2H, J=5.8, 4.8 Hz), 1.22 (d, 3H,J=1.6 Hz)

Example B14: Synthesis ofrac-(trans)-1-(4-aminopyrimidin-2-yl)-4-fluoropiperidin-3-ol

To a solution of 2-chloropyrimidin-4-amine (216 mg, 1.67 mmol) in IPAwere added rac-(3R,4R)-4-fluoropiperidin-3-ol hydrochloride (200 mg,1.67 mmol) and TEA (337 mg, 3.34 mmol) and heated to 100° C. and stirredovernight. LCMS showed the reaction was complete. The mixture was addedwater and extracted with EA. The organic phase was concentrated andpurified by FLASH. This is obtained the title compound, 180 mg (65%) asyellow solid.

Analytical Data: LC-MS: (ES, m/z)=213 [M+1].

Example B15: Synthesis ofrac-(1R,5S,8s)-3-(4-aminopyrimidin-2-yl)-3-azabicyclo[3.2.1]octan-8-ol

Step 1: Synthesis of (1R,5S,8s)-3-azabicyclo[3.2.1]octan-8-ol

A mixture of commercially availablerac-(1R,5S,8S)-3-benzyl-3-azabicyclo[3.2.1]octan-8-ol (200 mg, 920μmol), Pd/C (97.9 mg, 920 μmol) in MeOH (3 mL) was stirred at rt for 3h. The solid was filtered out and the filtrate was concentrated toafford the title compound (110 mg) as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=128 [M+1].

Step 2: Synthesis ofrac-(1R,5S,8s)-3-(4-aminopyrimidin-2-yl)-3-azabicyclo[3.2.1]octan-8-ol

A mixture of rac-(1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-ol (100 mg, 786μmol), 2-chloropyrimidin-4-amine (101 mg, 786 μmol), TEA (237 mg, 2.35mmol) in IPA (3 mL) was stirred at 100° C. for 16 h. The reactionmixture was concentrated and purified by preparative TLC (10% MeOH inDCM) to afford crude product 110 mg (64%) as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=221 [M+1].

Example B16: Synthesis ofrac-1-(1-(4-aminopyrimidin-2-yl)-3-fluoropyrrolidin-3-yl)ethanol

Step 1: Synthesis of rac-tert-butyl3-fluoro-3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate

To a solution ofrac-1-[(tert-butoxy)carbonyl]-3-fluoropyrrolidine-3-carboxylicacid (1 g,4.28 mmol), methoxy(methyl)amine (339 mg, 5.56 mmol), HATU (3.25 g, 8.56mmol) and DIPEA (1.65 g, 12.8 mmol) in DMF (30 mL) was stirred at rt for16 h. The reaction mixture was extracted with EA and the organic layerscombined and dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column with EA/PE(1:6) to give the title compound, 900 mg (76%) as a light-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=221 [M+1−56].

Step 2: Synthesis of rac-tert-butyl3-acetyl-3-fluoropyrrolidine-1-carboxylate

To a solution of rac-tert-butyl3-fluoro-3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (900 mg,3.25 mmol) in THF (20 mL) was added bromo(methyl)magnesium (7.7 mL, 2.5M, 16.2 mmol) at −60° C. under N₂. The reaction was warmed slowly to rtand stirred overnight. The reaction was quenched with aq NH₄Cl (10 mL),and extracted with EA and the organic layers combined and dried overanhydrous sodium sulfate and concentrated under vacuum to give the titlecompound 780 mg (crude) as a light-yellow oil.

Step 3: Synthesis of rac-tert-butyl3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate

To a solution of rac-tert-butyl3-acetyl-3-fluoropyrrolidine-1-carboxylate (780 mg, 3.37 mmol) in MeOH(10 mL) was added NaBH₄ (191 mg, 5.05 mmol) at 0° C. and stirred at rtfor 1.5 h. The reaction was concentrated under vacuum and extracted withEA and the organic layers combined and dried over anhydrous sodiumsulfate and concentrated under vacuum to give product 700 mg aslight-yellow oil.

Step 4: Synthesis of rac-1-(3-fluoropyrrolidin-3-yl)ethanol

To a solution of rac-tert-butyl3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylate (700 mg, 3 mmol) inDCM (5 mL) was added HCl/dioxane (3 mL) and stirred at rt for 2 h. Thereaction was concentrated under vacuum to give product 500 mg as alight-yellow solid.

Step 5: Synthesis ofrac-1-(1-(4-aminopyrimidin-2-yl)-3-fluoropyrrolidin-3-yl)ethanol

The solution of rac-1-(3-fluoropyrrolidin-3-yl)ethan-1-ol (550 mg, 4.13mmol), 2-chloropyrimidin-4-amine (535 mg, 4.13 mmol) and TEA (1.24 g,12.3 mmol) in IPA (6 mL) was heated to 100° C. and stirred overnight.The reaction was concentrated under vacuum and purified by TLC(DCM:MeOH=15:1) to give product 800 mg as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=227 [M+1].

Example B17: Synthesis ofrac-2-(4-aminopyrimidin-2-yl)-2-aza-bicyclo[2.2.1]heptan-5-ol

Step 1: Synthesis of rac-2-aza-bicyclo[2.2.1]heptan-5-ol

To a solution of rac-tert-butyl5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (500 mg, 2.34 mmol)in DCM (8 mL) were added TFA (226 mg, 2.34 mmol) and the mixture wasstirred at rt for 1 h LCMS showed the reaction was complete and solutionwas concentrated to give 450 mg of product that was used for the nextstep directly.

Analytical Data: LC-MS: (ES, m/z)=114 [M+1].

Step 2: Synthesis ofrac-2-(4-aminopyrimidin-2-yl)-2-aza-bicyclo[2.2.1]heptan-5-ol

The mixture of 2-chloropyrimidin-4-amine (200 mg, 1.54 mmol),rac-2-azabicyclo[2.2.1]heptan-5-ol (174 mg, crude) and TEA (311 mg, 3.08mmol) in IPA (5 mL) was stirred overnight at 110° C. LCMS showed thereaction was complete. The mixture was added water and extracted withEA. The organic phase was concentrated and purified by FLASH. Thisafforded the title compound, 180 mg as yellow solid.

Analytical Data: LC-MS: (ES, m/z)=207 [M+1].

Example B18: Synthesis ofrac-cis-1-(4-aminopyrimidin-2-yl)-4-fluoropiperidin-3-ol

Step 1: Synthesis of cis-4-fluoropiperidin-3-ol

Tert-butyl (cis)-4-fluoro-3-hydroxypiperidine-1-carboxylate (300 mg) wasdissolved into dioxane (1 mL). HCl in dioxane (4M, 2 mL) was added andstirred for 1 h. The reaction mixture was concentrated to afford thetitle compound a white solid (140 mg).

Analytical Data: LC-MS: (ES, m/z)=120 [M+1].

Step 2: Synthesis ofcis-1-(4-aminopyrimidin-2-yl)-4-fluoropiperidin-3-ol

The mixture of 2-chloropyrimidin-4-amine (129 mg),cis-4-fluoropiperidin-3-ol (118 mg), DIPEA (384 mg) in DMSO was stirredat 120° C. for 12 h. Water was added and the mixture was extracted withEA and purified by pre-TLC to (5% MeOH in DCM) afford the title compound(95 mg) as yellow solid.

Analytical Data: LC-MS: (ES, m/z)=213 [M+1].

Example B19: Synthesis of2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyrimidin-4-amine

To a solution of 2-chloropyrimidin-4-amine (1 g, 7.71 mmol) in IPA (12mL) were added 1,4-dioxa-8-azaspiro[4.5]decane (1.10 g, 7.71 mmol) andTEA (1.55 g, 15.4 mmol) and heated to 100° C. and stirred overnight. Themixture was added water and extracted with EA. The organic layer wasconcentrated and purified by FLASH (5% MeOH in DCM). It obtained thetitle compound, 1.5 g (82.8%) as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=237 [M+1].

Example B20: Synthesis of rac-tert-butyl4-(4-aminopyrimidin-2-yl)-2-(difluoromethyl)piperazine-1-carboxylate

The mixture of rac-tert-butyl 2-(difluoromethyl)piperazine-1-carboxylate(200 mg, 846 umol), 2-chloropyrimidin-4-amine (109 mg, 846 umol) andDIEA (326 mg, 2.53 umol) in DMSO (5 mL) was stirred at 120° C. for 3 h.The reaction mixture was diluted with water and extracted with EA. Theorganic layer was dried and purified by column chromatography(DCM:MeOH=20:1) to afford the title compound, (200 mg, 72%) as a yellowsolid.

Analytical Data: LC-MS: (ES, m/z)=330 [M+1].

Example B21: Synthesis of(3R,4R)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol and(3S,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol

To a solution of rac-trans-3-methylpiperidin-4-ol (800 mg, 6.94 mmol) inIPA (10 mL) was added 2-chloropyrimidin-4-amine (1.34 g, 10.4 mmol) andTEA (2.1 g, 20.8 mmol). The mixture was stirred at 100° C. for 8 h. Thereaction mixture was cooled to rt and concentrated under vacuum. Thecrude product was purified by flash with the following conditions:DCM:MEOH=10:1. This resulted in 1.2 g (83.3%) of the title compound as awhite solid.

Rac-trans-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol (1.2 g, 5.76mmol) were further separated by Chiral-Prep-HPLC with the followingconditions: Column: CHIRALPAK AD-H-TC001 SFC, 2*25 cm, 5 um; MobilePhase A: CO₂, Mobile Phase B: MEOH (2 mM NH₃-MEOH); Flow rate: 40mL/min; Gradient: 25% B; 220 nm to afford peak 1: 500 mg(3R,4R)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol or(3S,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol and peak 2: 460mg (3S,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol or(3R,4R)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol as a whitesolid.

Analytical Data: LC-MS: (ES, m/z)=209 [M+1].

Example B22: Synthesis ofrac-(cis)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-olandrac-(trans)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-ol

Step 1: Synthesis of tert-butyl3-fluoro-4-hydroxy-3,4-dimethylpiperidine-1-carboxylate

LiMe (27 mL, 43.2 mmol) was added into a mixture of rac-tert-butyl3-fluoro-3-methyl-4-oxopiperidine-1-carboxylate (5 g, 21.6 mmol, fromstep 2 of Example B1) in THF at 0° C. The reaction was stirred at 0° C.for 1 h. The reaction was quenched by H₂O and extracted by EA. Theorganic layer was evaporated in vacuum to afford a colorless oil (6 g,24.2 mmol) and used to next step directly.

Step 2: Synthesis of 3-fluoro-3,4-dimethylpiperidin-4-ol

Rac-tert-butyl 3-fluoro-4-hydroxy-3,4-dimethylpiperidine-1-carboxylate(6 g, 24.2 mmol) was placed in DCM/TFA (50 mL/15 mL). The mixture wasstirred at rt for 1 h. The solvent was removed by evaporation to give 6g of crude product.

Step 3: Synthesis ofrac-(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-olandrac-(3R,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-ol

DIPEA (7.85 g, 60.9 mmol) was added into3-fluoro-3,4-dimethylpiperidin-4-ol (3 g, crude) and2-chloropyrimidin-4-amine (2.62 g, 20.3 mmol) in DMSO (20 mL). Themixture was stirred at 100° C. for 16 h. Water was added and thesuspension was extracted with EA. The organic phase was concentrated andthe residue was purified by FLASH (50% EA in PE) to afford the titlecompound as a light-yellow solid (1.5 g).

1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-ol (1.5 g,6.24 mmol) was separated by SFC HPLC: Column: CHIRALPAK IC-3, 3*100 mm 3um; Mobile Phase A: Mobile Phase B: MeOH (0.1% DEA); Flow rate: 2mL/min; Gradient: 10% B; 220 nm; To afford peak 1:rac-cis-1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-ol(identified as cis by 2D NMR, 400 mg) as a white solid and peak 2:rac-trans-1-(4-aminopyrimidin-2-yl)-3-fluoro-3,4-dimethylpiperidin-4-ol(identified as trans by 2D NMR, 300 mg) as a white solid.

Analytical Data: LC-MS: (ES, m/z)=241 [M+1].

Example B23: Synthesis ofrac-(cis)-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol andrac-(trans)-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol

Step 1: Synthesis of rac-tert-butyl3-ethyl-3-fluoro-4-oxopiperidine-1-carboxylate

A solution of tert-butyl 3-ethyl-4-oxopiperidine-1-carboxylate (7.95 g,35 mmol, 1 equiv.) in DMF (35 mL) was added TEA (7.07 g, 70.0 mmol, 2equiv.), followed by TMSCl (5.67 g, 52.5 mmol, 1.50 equiv.) at rt. Thereaction was carried on at 120° C. for 18 h before quenching with sat.NaHCO₃. The mixture was extracted with MTBE. The organic layer wascombined and concentrated. The residue was dissolved in DMF (70 mL),Selectfluor (12.3 g, 35 mmol, 1 equiv) was added at 0° C. The mixturewas stirred for 2 h at rt and then quenched with brine. The mixture wasextracted with EA. The organic layer was combined and concentrated toafford a mixture of tert-butyl3-ethyl-3-fluoro-4-oxopiperidine-1-carboxylate, tert-butyl3-ethyl-5-fluoro-4-oxopiperidine-1-carboxylate and tert-butyl3-ethyl-4-oxopiperidine-1-carboxylate as yellow oil (6.5 g).

Step 2: Synthesis of rac-(9H-fluoren-9-yl)methyl3-ethyl-3-fluoro-4-oxopiperidine-1-carboxylate

A solution of tert-butyl 3-ethyl-3-fluoro-4-oxopiperidine-1-carboxylate(6.5 g, 26.4 mmol, 1 equiv.) in TFA (20 mL) and DCM (60 mL) was stirredat rt for 2 h. The mixture was concentrated and re-dissolved in DCM (120mL), TEA (13.3 g, 132 mmol, 5.00 equiv.) was added, followed by(9H-fluoren-9-yl)methyl carbonochloridate (10.2 g, 39.5 mmol, 1.50equiv.). The reaction was carried on at rt for 2 h. Sat. NaHCO₃ wasadded. The mixture was extracted with DCM. The organic layer wascombined and concentrated. The residue was purified by silica gel columnchromatography (DCM/EA=30:1) to afford the title compound (3.7 g, 30.53%over 2 steps) as a colorless syrup.

Analytical Data: LC-MS: (ES, m/z)=390 [M+23].

Step 3: Synthesis of rac-cis-(9H-fluoren-9-yl)methyl3-ethyl-3-fluoro-4-hydroxypiperidine-1-carboxylate andrac-trans-(9H-fluoren-9-yl)methyl3-ethyl-3-fluoro-4-hydroxypiperidine-1-carboxylate

Into a 25-mL round-bottom flask, was placed 9H-fluoren-9-ylmethyl3-ethyl-3-fluoro-4-oxopiperidine-1-carboxylate (500 mg, 1.361 mmol, 1equiv.), methanol (10 mL), NaBH₄ (102.97 mg, 2.722 mmol, 2 equiv.). Theresulting solution was stirred for 1 h at 0° C. The reaction was thenquenched by the addition of 1 mL of water. The resulting mixture wasconcentrated. The residue was applied onto silica gel column with EA/PE(1:1). This resulted in 200 mg of peak 1:rac-cis-(9H-fluoren-9-yl)methyl3-ethyl-3-fluoro-4-hydroxypiperidine-1-carboxylate (identified as cis by2D NMR) and 100 mg of peak 2: rac-trans-(9H-fluoren-9-yl)methyl3-ethyl-3-fluoro-4-hydroxypiperidine-1-carboxylate (identified as transby 2D NMR).

Analytical Data: LC-MS: (ES, m/z)=370 [M+1].

Step 4: Synthesis of rac-cis-3-ethyl-3-fluoropiperidin-4-ol andrac-trans-3-ethyl-3-fluoropiperidin-4-ol

Diethyl amine (3 mL) was added to the solution ofrac-cis-(9H-fluoren-9-yl)methyl3-ethyl-3-fluoro-4-hydroxypiperidine-1-carboxylate (200.0 mg, 0.54 mmol)in methanol (15 mL). The resulting solution was stirred for 2 h at 0° C.The resulting mixture was concentrated. This resulted in 60 mg (75%) ofthe title compound as light-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=148 [M+1].

Step 5: Synthesis ofrac-cis-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol andrac-trans-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol

The mixture of rac-cis-3-ethyl-3-fluoropiperidin-4-ol (1 g, 6.794 mmol,1 equiv.), 2-chloropyrimidin-4-amine (0.88 g, 6.794 mmol, 1 equiv.) andTEA (2.06 g, 20.38 mmol, 3 equiv.) IPA (10.00 mL) was stirred for 12 hat 100° C. The resulting mixture was concentrated. The residue wasapplied onto a silica gel column with DCM/MeOH (5:1). This resulted in 1g (61.3%) ofrac-cis-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol aslight-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=241 [M+1]; 1H-NMR (400 MHz, 6d-DMSO) δppm 7.72 (d, 1H, J=5.6 Hz), 6.35 (s, 2H), 5.69 (d, 1H, J=5.6 Hz), 4.88(d, 1H, J=6.5 Hz), 4.62 (ddd, 1H, J=14.0, 9.0, 1.9 Hz), 4.52-4.40 (m,1H), 3.63-3.42 (m, 1H), 3.08-2.86 (m, 2H), 1.84 (ddt, 1H, J=15.1, 9.4,7.5 Hz), 1.75-1.49 (m, 3H), 0.92 (t, 3H, J=7.6 Hz)

The mixture of rac-trans-3-ethyl-3-fluoropiperidin-4-ol (900 mg, 6.114mmol, 1 equiv.), 2-chloropyrimidin-4-amine (792.12 mg, 6.114 mmol, 1equiv.) and TEA (1856.15 mg, 18.343 mmol, 3 equiv.) in IPA (10.00 mL)was stirred for 12 h at 100° C. The resulting mixture was concentrated.The residue was applied onto a silica gel column with DCM/MeOHl (5:1).This resulted in 500 mg (34.03%) ofrac-trans-1-(4-aminopyrimidin-2-yl)-3-ethyl-3-fluoropiperidin-4-ol aslight-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=241 [M+1].

Example B24: Synthesis of(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol and(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol

The mixture of 2-chloropyrimidin-4-amine (700 mg, 5.42 mmol),rac-(3R,4S)-3-methylpiperidin-4-ol (900 mg, 5.42 mmol) and TEA (1.7 g,16.8 mmol) in IPA (10 mL) was stirred for 2 h at 100° C. The mixture wasconcentrated and the residue was purified by Prep-TLC with DCM/MeOH(20:1). This resulted in 700 mg (56%) ofrac-(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol as a yellowsolid. The rac-(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-olwas purified by Prep-HPLC with the following conditions Column:CHIRALPAK ID-3, 4.6*100 mm, 3 um; Mobile Phase A: Mobile Phase B: IPA(0.1% DEA; Flow rate: 4 mL/min; Gradient: 10% B; 220 nm; fractionscontaining the desired compound were evaporated to dryness to affordpeak 1: (3R,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol or (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol as a yellow solid(200 mg, 33%) and peak 2:(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol or(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-methylpiperidin-4-ol as alight-yellow solid (200 mg, 33%).

Analytical Data: LC-MS: (ES, m/z)=209 [M+1].

Example B25: Synthesis of2-(1,4-dioxa-9-azaspiro[5.5]undecan-9-yl)pyrimidin-4-amine

The mixture of 2-chloropyrimidin-4-amine (80 mg, 617 umol),1,4-dioxa-9-azaspiro[5.5]undecane (97.0 mg, 617 umol) and TEA (186 mg,1.85 mmol) in IPA (2 mL) was stirred at 100° C. for 3 h. The reactionmixture was diluted with water, extracted with EA and washed with brine.The organic layer was dried, evaporated and purified by Prep-TLC(DCM:MeOH=20:1) to afford the title compound (85 mg, 55%) as a yellowsolid.

Analytical Data: LC-MS: (ES, m/z)=251 [M+1].

Example B26: Synthesis of(3S,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-oland(3R,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-oland(3S,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-oland(3R,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol

Step 1: Synthesis of rac-tert-butyl5-fluoro-5-methyl-4-(triethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate

To a solution of rac-tert-butyl3-fluoro-3-methyl-4-oxopiperidine-1-carboxylate (4.7 g, 20.3 mmol) inTHF (30 mL) was added LiHDMS (30.4 mL, 30.4 mmol) at −70° C. and stirredat −30° C.˜−20° C. for 1 h. And then TESCl (6.11 g, 40.6 mmol) was addedand stirred at rt for 2 h. The reaction was quenched with water andextracted with EA. The organic layer was dried and concentrated. Theresidue was purified on silica column with 10% EtOAc in PE to afford thetitle compound (6.2 g, 88%) as a colorless oil.

Step 2: Synthesis of rac-tert-butyl3,5-difluoro-3-methyl-4-oxopiperidine-1-carboxylate

To a solution of rac-tert-butyl3-fluoro-3-methyl-4-[(triethylsilyl)oxy]-1,2,3,6-tetrahydropyridine-1-carboxylate(6.2 g, 17.9 mmol) in DMF (30 mL) was added SelectFluor (12.6 g, 35.8mmol) at 10° C. The mixture was stirred at rt. for 2 h. The reaction wasquenched with water, extracted with EA. The organic layer was dried andconcentrated. The residue was purified on silica gel column with 30%EtOAc in PE to afford the title compound (3 g, 67%) as a light-yellowoil.

Step 3: Synthesis of rac-tert-butyl3,5-difluoro-4-hydroxy-3-methylpiperidine-1-carboxylate

To a solution of rac-tert-butyl3,5-difluoro-3-methyl-4-oxopiperidine-1-carboxylate (3.5 g, 14.0 mmol)in MeOH was added NaBH₄ (1.06 g, 28 mmol) at ice-cream bath. The mixturewas stirred at rt for 3 h. The mixture was diluted with water, extractedwith EA and washed with brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 2.9 g(82.6%) of the title compound as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=196 [M+1−56].

Step 4: Synthesis of rac-3,5-difluoro-3-methylpiperidin-4-ol

Rac-tert-butyl 3,5-difluoro-4-hydroxy-3-methylpiperidine-1-carboxylate(1.6 g, 6.36 mmol) was added to the mixture of DCM (20 mL) and TFA (5mL). The resulting mixture was stirred at rt for 2 h. The mixture wasconcentrated under vacuum to afford the title compound as the salt (1.6g).

Analytical Data: LC-MS: (ES, m/z)=152 [M+1].

Step 5: Synthesis of(3S,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-oland(3R,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-oland(3S,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-oland(3R,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol

Into three 40-mL sealed tubes, was placed3,5-difluoro-3-methylpiperidin-4-ol (900 mg, 5.95 mmol) in DMSO (10 mL),2-chloropyrimidin-4-amine (1.6 g, crude, TFA salt) and DIEA (3.07 g,23.8 mmol). The resulting solution was stirred for 24 h at 120° C. Thereaction mixture was cooled to rt and diluted with water and extractedwith EA and concentrated under vacuum. The residue was purified byPrep-HPLC with Column: XBridge Prep OBD C18 Column, 30×150 mm Sum;Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1% NH3.H2O), Mobile Phase B:ACN; Flow rate: 60 mL/min; Gradient: 7 B to 20 B in 7 min; 254; 220 nm.This resulted in 380 mg of(3S,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-oland(3R,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-oland 350 mg(3S,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-oland(3R,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-olas a white solid. Isomers were further separated by SFC to give 150 mgpeak 1:(3S,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-olor(3R,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-oland 150 mg peak 2:(3R,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-olor(3S,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol.The second mixture was further separated by SFC to give 140 mg peak 1:(3S,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-olor(3R,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-oland 140 mg peak 2:(3R,4R,5R)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-olor(3S,4S,5S)-1-(4-aminopyrimidin-2-yl)-3,5-difluoro-3-methylpiperidin-4-ol

Analytical Data: LC-MS: (ES, m/z)=245 [M+1].

Example B27: Synthesis ofrac-2-(6-fluoro-1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyrimidin-4-amine

Step 1: Synthesis of Benzyl1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of 1,4-dioxa-8-azaspiro[4.5]decane (500 mg, 3.49 mmol),TEA (386 mg, 3.83 mmol) in THF (10 mL), benzyl carbonochloridate (386mg, 3.83 mmol) was added at 0° C. and stirred at rt for 3 h. Thereaction mixture was diluted with water and extracted with EA andsaturated brine. The organic layer was dried over Na₂SO₄, filtered,evaporated and purified by column chromatography (PE:EA=1:1) to affordbenzyl the title compound (800 mg) as a yellow oil.

Analytical Data: LC-MS: (ES, m/z)=278 [M+1].

Step 2: Synthesis of rac-benzyl6-fluoro-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate

H₂SO₄ (14.1 mg, 144 umol) was added to the mixture of benzyl1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (800 mg, 2.88 mmol) andSelectFluor (2.04 g, 5.76 mmol) in ACN (10 mL) at rt and stirred at 50°C. for 1 h, ethylene glycol (886 mg, 14.3 mmol) was added and stirredfor 2 h. The reaction mixture was diluted with water and extracted withEA and washed with brine. The organic layer was dried over Na₂SO₄,filtered, evaporated and purified by column chromatography (PE:EA=1:1)to afford the title compound (620 mg) as a yellow oil.

Analytical Data: LC-MS: (ES, m/z)=296 [M+1].

Step 3: Synthesis of rac-6-fluoro-1,4-dioxa-8-azaspiro[4.5]decane

The mixture of rac-benzyl6-fluoro-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (600 mg, 2.03mmol) and Pd/C (239 mg, 2.03 mmol) in MeOH (20 mL) was stirred at rt for2 h under hydrogen atmosphere. The reaction mixture was filtered,evaporated to afford the title compound (340 mg) as a brown oil.

Analytical Data: LC-MS: (ES, m/z)=162 [M+1].

Step 4: Synthesis ofrac-2-(6-fluoro-1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyrimidin-4-amine

The mixture of 2-chloropyrimidin-4-amine (180 mg, 1.38 mmol),rac-6-fluoro-1,4-dioxa-8-azaspiro[4.5]decane (333 mg, 2.07 mmol) and TEA(418 mg, 4.14 mmol) in IPA (5 mL) was stirred for 4 h at 100° C. Thereaction mixture was diluted with water, extracted with EA and washedwith brine. The organic layer was dried over Na₂SO₄, filtered,evaporated and purified by column chromatography (DCM:MeOH=30:1) toafford the title compound (200 mg) as a yellow solid.

Analytical Data:LC-MS: (ES, m/z)=255 [M+1].

Example B28: Synthesis of(3S,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol and(3R,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol

2-chloropyrimidin-4-amine (987 mg, 7.62 mmol) was added totrans-(3S,4S)-4-methoxypiperidin-3-ol (1.0 g, 7.62 mmol) and TEA (2.30g, 22.8 mmol) in IPA (20 mL) at rt. The mixture was stirred at 100° C.for 16 h. The mixture was concentrated under vacuum and the residue waspurified by a silica gel column with DCM: MeOH=20:1. The result in 1.2 gtrans-(3S,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol as acolorless oil.Trans-(3S,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol (1.2 g,5.35 mmol) was purified by Chiral-SFC with following conditions: Column:CHIRALPAK IC, 2*25 cm, 5 um; Mobile Phase A: CO₂, Mobile Phase B: EtOH(8 mmol/L NH₃.MeOH)-HPLC; Flow rate: 40 mL/min; Gradient: 25% B; 254 nm.The result in 450 mg peak 1:(3S,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol or(3R,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol as a whitesolid and 460 mg peak 2:(3R,4R)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol or(3S,4S)-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol as a whitesolid.

Analytical Data: LC-MS: (ES, m/z)=225 [M+1].

Example B29: Synthesis of2-(azetidin-3-ylmethylsulfonyl)-N,N-dimethylethanamine

Step 1: Synthesis of tert-butyl3-((2-hydroxyethylthio)methyl)azetidine-1-carboxylate

In a 50 mL flask, was added tert-butyl3-(iodomethyl)azetidine-1-carboxylate (3 g, 10.0 mmol) dissolved in THF(10 mL). To this was added 2-sulfanylethan-1-ol (781 mg, 10.0 mmol),K₂CO₃ (4.20 g, 30.0 mmol). The mixture was stirred overnight at rt. Thereaction was quenched with water and extracted with EA. The organiclayer was dried and concentrated to give the title compound (2.8 g)(crude) as brown oil.

Analytical Data: LC-MS: (ES, m/z)=248 [M+1].

Step 2: Synthesis of tert-butyl3-((2-hydroxyethylsulfonyl)methyl)azetidine-1-carboxylate

In a 50 mL flask, was added tert-butyl3-{[(2-hydroxyethyl)sulfanyl]methyl}azetidine-1-carboxylate (2.7 g, 1.2mmol) dissolved in THF/EtOH/H₂O (10 mL). To this was added Oxone (744mg, 1.2 mmol). The mixture was stirred for 3 h at rt. The reaction wasextracted with EA. The organic layer was dried and concentrated to givethe title compound (2.4 g crude) as a yellow solid.

Step 3: Synthesis of tert-butyl3-(vinylsulfonylmethyl)azetidine-1-carboxylate

Methanesulfonyl chloride (1.8 g) was added to the solution of tert-butyl3-[(2-hydroxyethanesulfonyl)methyl]azetidine-1-carboxylate (2.2 g) andTEA (2.5 g) in DCM (10 mL) at 0° C. The mixture was stirred for 3 h atrt. Water was added and extracted with EA. The organic layer was driedand concentrated to give the title compound (1.8 g) a brown solid.

Analytical Data: LC-MS: (ES, m/z)=206 [M+1-56].

Step 4: Synthesis of Tert-butyl3-((2-(dimethylamino)ethylsulfonyl)methyl)azetidine-1-carboxylate

In a 50 mL flask, was added tert-butyl3-[(ethenesulfonyl)methyl]azetidine-1-carboxylate (1.8 g) dissolved inDCM (10 mL). To this was added dimethylamine hydrochloride (1.2 g), TEA(2.3 g). The mixture was stirred for 3 h at rt. Water was added andextracted with DCM. The organic layers were combined and purified withDCM/MeOH (20/1) to the title compound (1.5 g) as brown solid.

Analytical Data: LC-MS: (ES, m/z)=307 [M+1].

Step 5: Synthesis of2-(azetidin-3-ylmethylsulfonyl)-N,N-dimethylethanamine

Tert-butyl3-((2-(dimethylamino)ethylsulfonyl)methyl)azetidine-1-carboxylate (1.5g, 4.9 mmol) was added to the solution of TFA (5 mL) in DCM (15 mL). Themixture was stirred for 3 h at rt. The solvent was removed under reducedpressure to afford the title compound as the trifluoroacetic acid salt,1.2 g (crude) as yellow solid.

Analytical Data: LC-MS: (ES, m/z)=207 [M+1].

Example B30: Synthesis of3-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-1,2,4-triazin-5-amine

Step 1: Synthesis of 3,5-dichloro-1,2,4-triazine

To a solution of 2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione (5.0 g,44.2 mmol) in toluene (20 mL) was added DIEA (17.1 g, 132.7 mmol) andPOCl₃ (27.1 g, 176.8 mmol) at rt. Then the solution was heated at 120°C. for 3 h. Excessive POCl₃ and toluene was removed under reducedpressure and the residue was diluted with EA and water. The organiclayer was washed with brine, dried over Na₂SO₄, concentrated to drynessto afford the crude product which was used for next step without furtherpurification (200 mg, crude).

Step 2: Synthesis of 3-chloro-1,2,4-triazin-5-amine

To a solution of 3,5-dichloro-1,2,4-triazine (200 mg, 1.33 mmol) in THF(5 mL) was added NH₃/MeOH (20 mL, 7.0 M) and the resulting mixture wasstirred at rt for 30 min; LC-MS showed that the reaction was completed.Evaporation to dryness and purified by Prep-HPLC to give the titlecompound (50 mg, 20% yield over two steps).

Analytical Data: LC-MS: (ES, m/z)=131 [M+1].

Step 3: Synthesis of3-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-1,2,4-triazin-5-amine

To a solution of 3-chloro-1,2,4-triazin-5-amine (30 mg, 229 umol) andDIPEA (88.4 mg, 686 umol) in DMSO (1 mL) was added1-oxa-7-azaspiro[3.5]nonane (29.1 mg, 229 umol) at rt. The mixture wasstirred for 2 h at 120° C. Water was added and the mixture was extractedby EA. The organic layer was combined and was dried by Na₂SO₄. Theorganic layer was concentrated and the residue was purified by Prep-TLCwith DCM/MeOH (20:1). This resulted in 30 mg (59%) the title compound asa light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=222 [M+1].

Example B31: Synthesis of3-(4-methoxypiperidin-1-yl)-1,2,4-triazin-5-amine

To a solution of 3-chloro-1,2,4-triazin-5-amine (30 mg, 229 umol) andDIEA (59 mg, 458 umol) in DMSO (1 mL) was added 4-methoxypiperidine(26.3 mg, 229 umol) at rt. The mixture was stirred for 2 h at 120° C.Water was added and the mixture was extracted by EA. The organic layerwas combined and was dried by Na₂SO₄. The organic layer was concentratedand the residue was purified by Prep-TLC with PE/EA (5:1). This resultedin 30 mg (62%) of the title compound as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=210 [M+1].

Example B32: Synthesis of2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

Step 1: Synthesis of (3R,4S)-tert-butyl3-fluoro-4-methoxypiperidine-1-carboxylate

To a solution of tert-butyl(3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (700 mg, 3.19 mmol)in THF (5 mL), NaH (152 mg, 3.82 mmol) was added at 0° C. MeI (497 mg,3.5 mmol) was added and the mixture was warmed to rt for and stirred for2 h. The reaction mixture was quenched with water, extracted with EA andwashed with brine. The organic layer was dried over Na₂SO₄, filtered andevaporated to afford the title compound (750 mg, crude) as a yellow oil.

Analytical Data: LC-MS: (ES, m/z)=178 [M+1-56].

Step 2: Synthesis of (3R,4S)-3-fluoro-4-methoxypiperidine

To a solution of tert-butyl(3R,4S)-3-fluoro-4-methoxypiperidine-1-carboxylate (750 mg, 3.21 mmol)in DCM (10 mL), TFA (2 mL) was added and stirred at rt for 3 h. Thereaction mixture was evaporated to afford the title compound (700 mgcrude) as a brown oil.

Step 3: Synthesis of2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

The mixture of (3R,4S)-3-fluoro-4-methoxypiperidine (700 mg, 5.25 mmol),2-chloropyrimidin-4-amine (488 mg, 3.76 mmol) and DIPEA (1.44 g, 11.2mmol) in DMSO (5 mL) was stirred at 100° C. for 2 h. The reactionmixture was diluted with water, extracted with EA and washed with brine.The organic layer was dried over Na₂SO₄, filtered, evaporated andpurified by column chromatography (50% EA in PE) to afford the titlecompound (550 mg) as a yellow solid.

Example B33: Synthesis of2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

Step 1: Synthesis of (3S,4R)-tert-butyl3-fluoro-4-methoxypiperidine-1-carboxylate

Sodium hydride (218.90 mg, 9.122 mmol, 4 equiv.) was added to tert-butyl(3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (500 mg, 2.280 mmol,1 equiv.) in THF (10 mL) at 0° C. After stirring for 20 min, methyliodide (1294.73 mg, 9.122 mmol, 4 equiv.) was added. The resultingsolution was stirred for additional 1 h at 0° C. The reaction was thenquenched by addition of 10 mL of water. The solids were filtered out.The resulting solution was extracted with EA and concentrated undervacuum. This resulted in 500 mg (94.1%) of the title compound aslight-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=178 [M+1−56].

Step 2: Synthesis of (3S,4R)-3-fluoro-4-methoxypiperidine

The solution of tert-butyl(3S,4R)-3-fluoro-4-methoxypiperidine-1-carboxylate (500 mg, 2.143 mmol,1 equiv.) in TFA/DCM (3/10 mL) was stirred for 1 h at rt. The resultingmixture was concentrated under vacuum to afford 500 mg (crude) of thetitle compound as a solid.

Step 3: Synthesis of2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

The mixture of (3S,4R)-3-fluoro-4-methoxypiperidine (3 g, 22.528 mmol, 1equiv.), 2-chloropyrimidin-4-amine (2.33 g, 0.018 mmol, 0.8 equiv.) andTEA (6.84 g, 0.068 mmol, 3 equiv.) in IPA (3 mL) was stirred for 12 h at100° C. The solvent was removed under vacuum and residue was purified byFLASH (5% MeOH in DCM) to give 3.3 g (66%) of the title compound as alight-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=227 [M+1]. 1H-NMR (400 MHz, 6d-DMSO) δppm 7.72 (d, 1H, J=5.6 Hz), 6.39 (s, 2H), 5.71 (d, 1H, J=5.6 Hz), 4.83(d, 1H, J=49.3 Hz), 4.60-4.49 (m, 1H), 4.29 (d, 1H, J=13.3 Hz),3.55-3.42 (m, 1H), 3.28 (d, 1H, J=13.3 Hz), 3.20-3.04 (m, 1H), 1.76-1.48(m, 2H)

Example B34: Synthesis of2-(8-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)pyrimidin-4-amine

The mixture of 8-oxa-3-aza-bicyclo[3.2.1]octane (226 mg, 2.0 mmol),2-chloropyrimidin-4-amine (260 mg, 2.0 mmol) and TEA (300 mg, 3.0 mmol)in IPA (5 mL) was stirred overnight at 100° C. The solvent was removedand the residue was purified by Prep-TLC (5% MeOH in DCM) to afford thetitle compound (300 mg, 73.8%) as yellow solid.

Analytical Data: LC-MS: (ES, m/z)=207 [M+1].

Example B35: Synthesis ofrac-1-(4-aminopyrimidin-2-yl)-2,4-dimethylpiperidin-4-ol

Step 1: Synthesis of rac-tert-butyl4-hydroxy-2,4-dimethylpiperidine-1-carboxylate

Methyllithium (822 mg, 37.4 mmol) was added dropwise to rac-tert-butyl2-methyl-4-oxopiperidine-1-carboxylate (4 g, 18.7 mmol) in THF at 0° C.The mixture was stirred at 0° C. for 1 h. The reaction was quenched withwater/ice and extracted with EA. Combined the organic layers andconcentrated under vacuum. This resulted in 4.2 g (98.1%) of the titlecompound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=230 [M+1].

Step 2: Synthesis of rac-2,4-dimethylpiperidin-4-ol

To a stirred solution of rac-tert-butyl4-hydroxy-2,4-dimethylpiperidine-1-carboxylate (4 g, 17.4 mmol) in DCMwas added TFA (10 mL). The mixture was stirred at rt for 2 h. Thereaction was concentrated under vacuum. The crude product was used tonest step directly.

Analytical Data: LC-MS: (ES, m/z)=130 [M+1].

Step 3: Synthesis ofrac-1-(4-aminopyrimidin-2-yl)-2,4-dimethylpiperidin-4-ol

To a stirred solution of rac-2,4-dimethylpiperidin-4-ol (2 g, 15.4 mmol)and 2-chloropyrimidin-4-amine (2.18 g, 16.9 mmol) in NMP was added DIEA(3.97 g, 30.8 mmol). The mixture was stirred overnight at 150° C. Aftercooling to rt, the reaction was extracted with DCM/MeOH (10:1). Theresidue was purified by Prep-TLC with DCM/MeOH (10:1). This resulted in0.2 g of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z)=223 [M+1].

Example B36: Synthesis ofrac-2-(6-oxa-3-aza-bicyclo[3.2.1]octan-3-yl)pyrimidin-4-amine

A mixture of 2-chloropyrimidin-4-amine (100 mg, 0.7719 mmol),rac-6-oxa-3-azabicyclo[3.2.1]octane hydrochloride (115 mg, 0.7719 mmol),TEA (233 mg, 2.31 mmol) in IPA (3 mL) was stirred at 100° C. for 3 h.The solution was concentrate and the residue was purified on prep-TLC(DCM:MeOH=10:1) to afford the title compound (100 mg) as a white solid.

Analytical Data: LC-MS: (ES, m/z)=207 [M+1].

Example B37: Synthesis of tert-butyl3-(azetidin-3-ylmethylsulfonyl)azetidine-1-carboxylate

Step 1: Synthesis of benzyl3-((methylsulfonyloxy)methyl)azetidine-1-carboxylate

Into a 100 mL round bottom flask was placed benzyl3-(hydroxymethyl)azetidine-1-carboxylate (1.2 g, 5.42 mmol) in DCM (20mL), TEA (822 mg, 8.13 mmol) and methanesulfonyl chloride (620 mg, 5.42mmol). The resulting solution was stirred at rt for 6 h. The solutionwas washed with water and purified by Prep-TLC (20% EA in PE). Theresulted in 1.0 g of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z)=300 [M+1].

Step 2: Synthesis of tert-butyl3-((1-(benzyloxycarbonyl)azetidin-3-yl)methylthio)azetidine-1-carboxylate

The mixture of benzyl3-[(methanesulfonyloxy)methyl]azetidine-1-carboxylate (530 mg, 1.77mmol), tert-butyl 3-sulfanylazetidine-1-carboxylate (335 mg, 1.77 mmol)and Cs₂CO₃ (1.15 g, 3.54 mmol) in DMF (2 mL) was stirred at 100° C. for2 h. Water was added and the mixture was extracted by EA. The organicphase was concentrated to afford 480 mg of the title compound as a whitesolid.

Analytical Data: LC-MS: (ES, m/z)=293 [M+1−100].

Step 3: Synthesis of tert-butyl3-((1-(benzyloxycarbonyl)azetidin-3-yl)methylsulfonyl)azetidine-1-carboxylate

Oxone (4.21 g, 6.86 mmol) was added to the solution of benzyl3-[({1-[(tert-butoxy)carbonyl]azetidin-3-yl}sulfanyl)methyl]azetidine-1-carboxylate(900 mg, 2.29 mmol) in EtOH/THF/H₂O (3/3/3 mL). The resulting solutionwas stirred at rt for 2 h. The resulting solution was extracted by EAand purified by Prep-TLC with DCM/MeOH (100:1) to afford 680 mg of thetitle compound as white solid.

Analytical Data: LC-MS: (ES, m/z)=325 [M+1−100].

Step 4: Synthesis of tert-butyl3-(azetidin-3-ylmethylsulfonyl)azetidine-1-carboxylate

Benzyl3-[({1-[(tert-butoxy)carbonyl]azetidin-3-yl}sulfonyl)methyl]azetidine-1-carboxylate(660 mg, 1.55 mmol) and Pd/C (199 mg, 1.55 mmol) in MeOH (12 mL) werestirred under an atmosphere of hydrogen at rt for 4 h. The solid wasfiltered out, mother solvent was concentrated under reduced pressure togive the title compound (480 mg) as a white solid.

Analytical Data: LC-MS: (ES, m/z)=291 [M+1].

Example B38: Synthesis of rac-1-(4-aminopyrimidin-2-yl)azepan-4-ol

A mixture of rac-azepan-4-ol hydrochloride (150 mg, 0.9892 mmol),2-chloropyrimidin-4-amine (128 mg, 0.989 mmol) and TEA (199 mg, 1.97mmol) in IPA (15 mL) was stirred at 100° C. for 3 h. The reactionmixture was concentrated and purified by preparative TLC (DCM: MeOH=5:1)to afford the title compound (90 mg) as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=209 [M+1].

Example B39: Synthesis of(S)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine and(R)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

Step 1: Synthesis of tert-butyl3,3-difluoro-4-methoxypiperidine-1-carboxylate

NaH (20.23 mg, 0.843 mmol, 2 equiv.) was added to tert-butyl3,3-difluoro-4-hydroxypiperidine-1-carboxylate (100 mg, 0.422 mmol, 1equiv.) in DMF (5 mL) at 0° C. After stirring for 30 min, MeI (89.74 mg,0.632 mmol, 1.5 equiv.) was added and the mixture was stirred for 2 h atrt. The reaction was then quenched by the addition of 10 mL of water.The resulting solution was extracted with EA and concentrated. Thisresulted in 150 mg (crude) of the title compound as a light-yellowsolid.

Analytical Data: LC-MS: (ES, m/z)=252 [M+1].

Step 2: Synthesis of 3,3-difluoro-4-methoxypiperidine

The solution of tert-butyl3,3-difluoro-4-methoxypiperidine-1-carboxylate (300 mg, 1.194 mmol) in4M HCl/dioxane (5 mL) and DCM (15 mL) was stirred for 12 h at rt. Theresulting mixture was concentrated. This resulted in 280 mg (crude) ofthe title compound as the HCl salt as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=152 [M+1].

Step 3: Synthesis of(S)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine and(R)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine

The mixture of 3,3-difluoro-4-methoxypiperidine (1.5 g, 9.923 mmol, 1equiv.), 2-chloropyrimidin-4-amine (1.29 g, 9.923 mmol, 1 equiv.) andTEA (3.01 g, 29.77 mmol, 3 equiv.) in IPA (10 mL) was stirred for 3 hrat 100° C. The resulting mixture was concentrated. The residue wasapplied onto a silica gel column with EA/PE (1:1). This resulted in 1.1g (45.4%) of the title compound as a yellow solid.

2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine was separatedby prep-Chiral SFC by following conditions: Column name: CHIRALCEL OJ-3,4.6*50 mm, 3 um; Co-Solvent: MeOH (0.1% DEA) Gradient (B %): 10% to 50%in 4.0 min, hold 2.0 min at 50%; Back Pressure (psi): 1500.000; Flow(mL/min) to afford peak 1:(S)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine or(R)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (500 mg)as pale-yellow solid and peak 2:(R)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine or(S)-2-(3,3-difluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (500 mg)as pale-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=245 [M+1].

Example B40: Synthesis ofrac-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-5,5-dimethylpiperidin-4-ol

Step 1: Synthesis of rac-tert-butyl5-fluoro-3,3-dimethyl-4-oxopiperidine-1-carboxylate

To a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate(7.5 g, 32.9 mmol) and TEA (13.2 g, 131 mmol) in toluene was addedTMSOTf (14.6 g, 65.8 mmol) at 0° C. under N₂ atmosphere. The mixture wasstirred for 2 h at rt. The mixture was extracted by EA and water. Theorganic layer was dried over Na₂SO₄ and concentrated under vacuum. Thecrude product was used directly for next step.

To a solution of tert-butyl3,3-dimethyl-4-[(trimethylsilyl)oxy]-1,2,3,6-tetrahydropyridine-1-carboxylate(1.2 g, 4.0 mmol) in ACN was added Selectfluor (1.55 g, 4.4 mmol) at 0°C. and the mixture was stirred for 1 h at 0° C. Water was added and themixture was extracted by EA. The organic layer was combined and wasdried over Na₂SO₄. The organic layer was concentrated and the residuewas purified by flash with PE/EA (5:1). This resulted in 500 mg (51%) ofthe title compound as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=246 [M+1].

Step 2: Synthesis of tert-butyl3,3-difluoro-5,5-dimethyl-4-oxopiperidine-1-carboxylate

To a solution of rac-tert-butyl5-fluoro-3,3-dimethyl-4-oxopiperidine-1-carboxylate (100 mg, 407 umol)in THF was added LiHMDS (46.4 mg, 814 umol) at −78° C. under N₂atmosphere. The mixture was stirred for 10 min at −78° C. and NFSI (117mg, 610 umol) was added. The resulting mixture was stirred for 2 h. Themixture was extracted by EA and water. The organic layer wasconcentrated and the residue was purified by Prep-TLC with PE/EA (5:1).This resulted in 60 mg (56%) of the title compound as a light-yellowsolid.

Analytical Data: LC-MS: (ES, m/z)=208 [M+1−56].

Step 3: Synthesis of rac-tert-butyl3,3-difluoro-4-hydroxy-5,5-dimethylpiperidine-1-carboxylate

To a solution of tert-butyl3,3-difluoro-5,5-dimethyl-4-oxopiperidine-1-carboxylate (80 mg, 303umol) in MeOH was added NaBH₄ (45.9 mg, 1.21 mmol) at rt. The mixturewas stirred for 2 h at rt. The mixture was extracted by EA and water.The organic layer was concentrated under vacuum. The crude product 75 mgwas used directly for next step.

Analytical Data: LC-MS: (ES, m/z)=210 [M+1−56].

Step 4: Synthesis of rac-3,3-difluoro-5,5-dimethylpiperidin-4-ol

Rac-tert-butyl3,3-difluoro-4-hydroxy-5,5-dimethylpiperidine-1-carboxylate (75 mg, 282umol) was added to DCM/TFA (5 mL/2 mL) at rt. The mixture was stirredfor 2 h at rt. The resulting mixture was concentrated under vacuum togive 40 mg (86%) of the title compound as a brown liquid.

Analytical Data: LC-MS: (ES, m/z)=166 [M+1].

Step 5: Synthesis of rac-tert-butyl2-(3,3-difluoro-4-hydroxy-5,5-dimethylpiperidin-1-yl)pyrimidin-4-ylcarbamate

The mixture of rac-3,3-difluoro-5,5-dimethylpiperidin-4-ol (100 mg, 605umol), tert-butyl N-(2-bromopyrimidin-4-yl)-N-[(tertbutoxy)carbonyl]carbamate (226 mg, 605 umol), CuI (57.3 mg, 302 umol),L-Proline (6.95 mg, 60.5 umol) and K₃PO₄ (383 mg, 1.81 mmol) in DMSO wasstirred for 2 h at 100° C. under N₂ atmosphere. Water was added and themixture was extracted with EA. The organic phase was concentrated andthe residue was purified by Prep-TLC with DCM/MeOH (20:1). This resultedin 100 mg (36%) of product as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=359 [M+1].

Step 6: Synthesis ofrac-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-5,5-dimethylpiperidin-4-ol

Rac-tert-butyl-N-[(tert-butoxy)carbonyl]-N-[2-(3,3-difluoro-4-hydroxy-5,5-dimethylpiperidin-1-yl)pyrimidin-4-yl]carbamate (200 mg, 436 umol) in DCM/TFA (10/3 mL) wasstirred for 2 h at rt. The solvent was concentrated under vacuum to give100 mg (90%) of the title compound as a brown solid.

Analytical Data: LC-MS: (ES, m/z)=259 [M+1].

Example B41: Synthesis ofrac-1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-3-methylpiperidin-4-ols

To a solution of 3-chloro-1,2,4-triazin-5-amine (280 mg, 2.14 mmol) andTEA (648 mg, 6.42 mmol) in IPA (5 mL) was added3-fluoro-3-methylpiperidin-4-ol (Step 4, B1; 284 mg, 2.14 mmol) at rt.The mixture was stirred for 2 h at 100° C. The solvent was removed andthe residue was purified by Prep-TLC with PE/EA (5:1). This resulted in260 mg (53%) of1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-3-methylpiperidin-4-ol as ayellow solid. The product was purified by Column: XBridge Shield RP18OBD Column, 30*150 mm, 5 um; Mobile Phase A: Water (0.05% NH₃H₂O),Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5 B to 10 B in 7min; 254/220 nm. This resulted in 90 mg ofrac-cis-1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-3-methylpiperidin-4-oland 30 mg ofrac-trans-1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-3-methylpiperidin-4-ol.Both are yellow solid.

Analytical Data: LC-MS: (ES, m/z)=228 [M+1].

Example B42: Synthesis ofrac-(cis)-1-(4-aminopyrimidin-2-yl)-4-methoxy-3-methylpiperidin-3-ol andrac-(cis)-1-(4-aminopyrimidin-2-yl)-3-methoxy-3-methylpiperidin-4-ol

Step 1: Synthesis of rac-(cis)-tert-butyl3,4-dihydroxy-3-methylpiperidine-1-carboxylate

To a mixture of tert-butyl5-methyl-1,2,3,6-tetrahydropyridine-1-carboxylate (200 mg, 1012 μmop,NMO (142.2 mg, 1214 μmol) in acetone (6 mL) and water (2 mL) was addedK₂Os₄.2H₂O (37.4 mg, 101.2 μmol). The mixture was stirred at rt for 2 h.The reaction mixture was extracted with EA. The organic layer was driedover Na₂SO₄. Filtered and concentrated to dryness to afford the titlecompound (180 mg) as a dark-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=176 [M+1−56].

Step 2: Synthesis of rac-(cis)-tert-butyl3-hydroxy-4-methoxy-3-methylpiperidine-1-carboxylate

MeI (367 mg, 2.59 mmol) was added to the mixture of Ag₂O (399 mg, 1.72mmol) and tert-butyl(cis)-3,4-dihydroxy-3-methylpiperidine-1-carboxylate (200 mg, 864 μmol)in DMF (20 mL) at rt. The mixture was stirred at rt for 2d. The solidwas filtered out and the filtrate was diluted with EA, washed with H₂O.The organic layer was dried over Na₂SO₄ and concentrated under vacuum toafford 160 mg rac-tert-butyl(cis)-3-hydroxy-4-methoxy-3-methylpiperidine-1-carboxylate mixed withrac-(cis)-tert-butyl4-hydroxy-3-methoxy-3-methylpiperidine-1-carboxylate as a colorless oil,used in next step without further purification.

Analytical Data: LC-MS: (ES, m/z)=190 [M+1-56].

Step 3: Synthesis of rac-(cis)-4-methoxy-3-methylpiperidin-3-ol

TFA (5 mL) was added dropwise to rac-tert-butyl(cis)-3-hydroxy-4-methoxy-3-methylpiperidine-1-carboxylate mixed withrac-(cis)-tert-butyl4-hydroxy-3-methoxy-3-methylpiperidine-1-carboxylate (160 mg, 652 μmol)in DCM (15 mL) at rt. The resulting mixture was stirred at rt for 2 h.The resulting mixture was concentrated under vacuum to afford 100 mgrac-(cis)-4-methoxy-3-methylpiperidin-3-ol mixed withrac-(cis)-3-methoxy-3-methylpiperidin-4-ol as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=146 [M+1].

Step 4: Synthesis ofrac-(cis)-1-(4-aminopyrimidin-2-yl)-4-methoxy-3-methylpiperidin-3-ol andrac-(cis)-1-(4-aminopyrimidin-2-yl)-3-methoxy-3-methylpiperidin-4-ol

2-chloropyrimidin-4-amine (100 mg, 771 μmol) was added to TEA (388 mg,385 mmol) and rac-(cis)-4-methoxy-3-methylpiperidin-3-ol (111 mg, 771μmop/rac-(cis)-3-methoxy-3-methylpiperidin-4-ol in IPA at rt. Themixture was heated to 100° C. for 16 h. The mixture was concentratedunder vacuum. The residue was purified by Prep-TLC with DCM: MeOH=25:1.The result in 120 mgrac-(cis)-1-(4-aminopyrimidin-2-yl)-4-methoxy-3-methylpiperidin-3-olmixed withrac-(cis)-1-(4-aminopyrimidin-2-yl)-3-methoxy-3-methylpiperidin-4-ol asa brown oil.

Analytical Data: LC-MS: (ES, m/z)=239 [M+1].

Example B43: Synthesis of3-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,2,4-triazin-5-amine

To a solution of (3R,4S)-3-fluoro-4-methoxypiperidine (60 mg, 450 umol)and DIEA (174 mg, 1.35 mmol) in DMSO (2 mL) was added3-chloro-1,2,4-triazin-5-amine (64.6 mg, 495 umol) at rt. The mixturewas stirred for 2 h at 120° C. Water was added the mixture was extractedby EA. The organic layer was concentrated and purified by Prep-TLC withPE/EA (5:1). This resulted in 40 mg (39%) of the title compound as ayellow solid.

Analytical Data:LC-MS: (ES, m/z)=228 [M+1].

Example B44: Synthesis of2-(1-(4-aminopyrimidin-2-yl)piperidin-4-yloxy)ethanol

The mixture of 2-chloropyrimidin-4-amine (400 mg, 3.08 mmol),2-(piperidin-4-yloxy)ethan-1-ol (447 mg, 3.08 mmol) and TEA (933 mg,9.24 mmol) in IPA (10 mL) was stirred for 12 h at 100° C. The reactionmixture was diluted with water, extracted with EA. The organic layer wasdried over Na₂SO₄, filtered, evaporated and purified by columnchromatography (DCM:MeOH=20:1) to afford the title compound (270 mg) asa yellow solid.

Analytical Data: LC-MS: (ES, m/z)=239 [M+1].

Example B45: Synthesis ofrac-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-yl)methanol

Step 1: Synthesis of rac-1-tert-butyl 3-methyl4-methoxypiperidine-1,3-dicarboxylate

NaH (1.3 g, 34.5 mmol) was added to the solution of rac-1-tert-butyl3-methyl 4-hydroxypiperidine-1,3-dicarboxylate (6.0 g, 23.0 mmol) in DMF(50 mL) at 0° C. After stirring for 10 min, iodomethane (4.8 g, 34.5mmol) was added. The mixture was stirred overnight at rt. Water wasadded and the mixture was extracted with EA. The organic phase waswashed with water, dried and concentrated. The residue was purified byFLASH (20% EA in PE) to give the title compound 3.0 g (47%) as colorlessoil.

Analytical Data:LC-MS: (ES, m/z)=274 [M+1].

Step 2: Synthesis of rac-tert-butyl3-(hydroxymethyl)-4-methoxypiperidine-1-carboxylate

LiBH₄ (2M in THF, 15 mmol) was added to the solution of rac-1-tert-butyl3-methyl 4-methoxypiperidine-1,3-dicarboxylate (2 g, 7.3 mmol) in THF(40 mL) at 0° C. The mixture was stirred for 2 h at rt. Water was addedand the mixture was extracted with EA. The organic phase was washed withwater, dried and concentrated to give the title compound 1.2 g (67%) ascolorless oil.

Analytical Data: LC-MS: (ES, m/z)=246 [M+1].

Step 3: Synthesis of rac-(4-methoxypiperidin-3-yl)methanol

Rac-tert-butyl 3-(hydroxymethyl)-4-methoxypiperidine-1-carboxylate 1.2 gwas added to the solution of TFA/DCM (20 mL/6 mL). The mixture wasstirred for 2 h at rt. The solvent was removed under reduced pressure togive the title compound trifluoroacetic acid salt 700 mg as yellow oil.

Analytical Data: LC-MS: (ES, m/z)=146 [M+1].

Step 4: Synthesis ofrac-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-yl)methanol

The mixture of rac-(4-methoxypiperidin-3-yl)methanol (700 mg),2-chloropyrimidin-4-amine (376 mg, 2.89 mmol) and TEA (578 mg, 5.78mmol) in IPA was stirred overnight at 100° C. The solvent was removedand the residue was purified by Prep-TLC (5% MeOH in DCM) to affordrac-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-yl)methanol 400 mgas pale-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=239 [M+1].

Example B46: Synthesis of(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methanol

Step 1: Synthesis of (4-methoxypiperidin-4-yl)methanol

To a solution of 4-methoxypiperidine-4-carboxylic acid hydrochloride(200 mg, 1.02 mmol) in THF (25 mL) was added LiAlH₄ (116 mg, 3.06 mmol).The mixture was stirred at 60° C. for 16 h. The reaction mixture wasquenched with ice-water. The resulting mixture was washed with EA. Theaqueous layer was filtered and concentrated to dryness to afford thetitle compound (400 mg, crude) as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=146 [M+1].

Step 2: Synthesis of(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methanol

The mixture of (4-methoxypiperidin-4-yl)methanol (400 mg, crude),4-chloropyrimidin-2-amine (130 mg, 1.01 mmol), TEA (306 mg, 3.03 mmol)in IPA (25 mL) was stirred at 100° C. for 2 h. The mixture wasconcentrated and the residue was purified on prep-TLC (EA:PE=2:1) toafford the title compound (35 mg) as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=239 [M+1].

Example B47: Synthesis ofrac-1-(4-aminopyrimidin-2-yl)-2-methylpiperidin-4-ol

The mixture of rac-2-methylpiperidin-4-ol (575 mg, 5.0 mmol),2-chloropyrimidin-4-amine (645 mg, 5.0 mmol) and TEA (1000 mg, 10 mmol)in IPA (5 mL) was stirred overnight at 100° C. The solvent was removedunder reduced pressure. The residue was purified by Prep-TLC (5% MeOH inDCM) to afford the title compound 200 mg as yellow solid.

Analytical Data: LC-MS: (ES, m/z)=209 [M+1].

Example B48: Synthesis of tert-butyl2-(1-(4-aminopyrimidin-2-yl)piperidin-4-yloxy)ethylcarbamate

Step 1: Synthesis of tert-butyl 2-(piperidin-4-yloxy)ethylcarbamate

The mixture of tert-butyl 2-(pyridin-4-yloxy)ethylcarbamate (200 mg,0.84 mmol) and PtO₂ (30 mg) in AcOH (5 mL) was stirred overnight at 50°C. under 5 atm of H2 atmosphere. The solvent was removed under reducedpressure and reside was dilute with MeOH. The solid was filtered out andthe filtrate was concentrated to afford 250 mg of crude the titlecompound as colorless oil.

Analytical Data: LC-MS: (ES, m/z)=245 [M+1].

Step 2: Synthesis of Tert-butyl2-(1-(4-aminopyrimidin-2-yl)piperidin-4-yloxy)ethylcarbamate

The mixture of 250 mg of crude tert-butyl2-(piperidin-4-yloxy)ethylcarbamate, 2-chloropyrimidin-4-amine (129 mg,1.0 mmol) and TEA (200 mg, 2.0 mmol) in DMSO (1 mL) was stirredovernight at 120° C. Water was added and the mixture was extracted withEA. The organic phase was washed, concentrated and purified by Prep-TLC(5% MeOH in DCM) to afford 70 mg of the title compound as yellow oil.

Analytical Data: LC-MS: (ES, m/z)=338 [M+1].

Example B49: Synthesis ofrac-cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile andrac-trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile

Step 1: Synthesis of rac-tert-butyl3-carbamoyl-4-methoxypiperidine-1-carboxylate

To a solution ofrac-1-[(tert-butoxy)carbonyl]-4-methoxypiperidine-3-carboxylic acid (500mg, 1.92 mmol), DIPEA (744 mg, 5.76 mmol), ammonia water (10 mL) andHATU (1.09 g, 2.88 mmol) in DCM (30 mL) was stirred for 1 h at rt. Themixture was extracted with DCM, dried and concentrated to afford thetitle compound (500 mg) as colorless oil.

Analytical Data: LC-MS: (ES, m/z)=259[M+1].

Step 2: Synthesis of rac-tert-butyl3-cyano-4-methoxypiperidine-1-carboxylate

TFAA (810 mg, 3.86 mmol) was added to a solution of rac-tert-butyl3-carbamoyl-4-methoxypiperidine-1-carboxylate (500 mg, 1.93 mmol) andTEA (585 mg, 5.79 mmol) in DCM (25 mL). The mixture was stirred for 2 hat rt. The resulting solution was washed with water and dried overNa₂SO₄. This is resulted the title compound (400 mg) as colorless oil.

Analytical Data: LC-MS: (ES, m/z)=185 [M+1−56].

Step 3: Synthesis of rac-4-methoxypiperidine-3-carbonitrile

To a solution of rac-tert-butyl3-cyano-4-methoxypiperidine-1-carboxylate (400 mg, 1.66 mmol) in DCM (10mL) was added TFA (5 mL). After 1 h, the solvent was removed byconcentration. This is resulted the title compound (500 mg) as alight-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=141[M+1].

Step 4: Synthesis ofrac-cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile andrac-trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile

A mixture of 2-chloropyrimidin-4-amine (461 mg, 3.56 mmol),rac-4-methoxypiperidine-3-carbonitrile (500 mg, 3.56 mmol), DIPEA (1.37g, 10.6 mmol) in DMSO (20 mL) was stirred at 120° C. for 3 h. Thereaction mixture was purified on prep-HPLC, Column: XBridge Shield RP18OBD Column, 30*150 mm, Sum; Mobile Phase A: Water (0.05% NH₃H₂O), MobilePhase B: ACN; Flow rate: 60 mL/min; Gradient: 13 B to 23 B in 7 min;254/220 nm. This resulted inrac-cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile (35mg) as a colorless oil andrac-trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile(50 mg) as a colorless oil.

rac-cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile

Analytical Data: LC-MS: (ES, m/z)=234 [M+1]; 1H-NMR (300 MHz, 3d-CD₃Cl)δ ppm 7.94 (d, 1H, J=5.6 Hz), 5.81 (d, 1H, J=5.7 Hz), 4.68 (s, 2H), 4.37(dd, 1H, J=13.4, 7.0 Hz), 4.14-4.00 (m, 1H), 3.85 (dd, 1H, J=13.1, 3.6Hz), 3.68-3.57 (m, 2H), 3.49 (s, 3H), 3.04 (dtd, 1H, J=6.7, 3.8, 2.0Hz), 1.99-1.71 (m, 2H)

rac-trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidine-3-carbonitrile

Analytical Data: LC-MS: (ES, m/z)=234 [M+1]; 1H-NMR (300 MHz, 3d-CD₃Cl)δ ppm 7.93 (d, 1H, J=5.6 Hz), 5.82 (d, 1H, J=5.6 Hz), 4.78-4.71 (m, 1H),4.69 (s, 2H), 4.51-4.37 (m, 1H), 3.61-3.51 (m, 1H), 3.49 (s, 3H), 3.40(dd, 1H, J=13.4, 9.5 Hz), 3.19 (ddd, 1H, J=13.6, 10.4, 3.1 Hz), 2.64(td, 1H, J=9.1, 4.0 Hz), 2.21-2.07 (m, 1H), 1.53-1.34 (m, 1H)

Example B50: Synthesis ofrac-1-(4-aminopyrimidin-2-yl)-3-methoxypiperidin-4-ol

Step 1: Synthesis of rac-tert-butyl4-hydroxy-3-methoxypiperidine-1-carboxylate

NaBH₄ (395 mg, 10.4 mmol) was added to a solution of rac-tert-butyl3-methoxy-4-oxopiperidine-1-carboxylate (2 g, 8.72 mmol) in THF (50 mL)at 0° C. and stirred at rt for 2 h. The reaction mixture was dilutedwith water, extracted with EA and washed with brine. The organic layerwas dried over Na₂SO₄, filtered, evaporated to afford the title compound(2 g, crude) as a yellow semi-solid.

Analytical Data: LC-MS: (ES, m/z)=232 [M+1].

Step 2: Synthesis of rac-3-methoxypiperidin-4-ol

The solution of rac-tert-butyl4-hydroxy-3-methoxypiperidine-1-carboxylate (1 g, 4.32 mmol) inHCl/dioxane (50 mL) was stirred at rt for 3 h. The reaction mixture wasevaporated to afford the title compound (700 mg, crude) as a yellowsemi-solid.

Analytical Data: LC-MS: (ES, m/z)=132 [M+1].

Step 3: Synthesis ofrac-1-(4-aminopyrimidin-2-yl)-3-methoxypiperidin-4-ol

The mixture of rac-2-chloropyrimidin-4-amine (200 mg, 1.54 mmol),3-methoxypiperidin-4-ol (700 mg, 5.33 mmol) and TEA (1.24 g, 12.3 mmol)in IPA (8 mL) was stirred at 100° C. for 12 h. The reaction mixture wasdiluted with water (100 mL), and extracted with EA (150 mL×3) and washedwith brine (50 mL). The organic layer was dried over Na₂SO₄, filtered,evaporated and purified by column chromatography (EA) to afford thetitle compound (220 mg) as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=225 [M+1].

Example B51: Synthesis of2-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol

Step 1: Synthesis of (3R,4S)-tert-butyl3-fluoro-4-(2-hydroxyethoxy)piperidine-1-carboxylate

NaH (455 mg, 11.4 mmol) was added to tert-butyl(3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (1.0 g, 4.56 mmol) inDMF 10 mL at 0° C. After stirring for 20 min,(2-bromoethoxy)(tert-butyl)dimethylsilane (3.25 g, 13.6 mmol) was addedand the resulting mixture was stirred at rt for 16 h. The mixture wasdiluted with EA and washed with brine. The organic layer was dried withNa₂SO₄ and concentrated under vacuum. The residue was purified by aFLASH with PE:EA=10:1 to afford 1.1 g the title compound as a colorlessoil.

Step 2: Synthesis of2-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol

TFA (5 mL) was added to tert-butyl(3R,4S)-4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3-fluoropiperidine-1-carboxylate(1.1 g, 2.91 mmol) in DCM (20 mL) at rt. The resulting mixture wasstirred at rt for 1 h. The mixture was concentrated under vacuum and theresidue was mixed with 2-chloropyrimidin-4-amine (317 mg, 2.45 mmol) andDIEA (1.26 mg, 9.80 mmol) in DMSO (10 mL). The mixture was heated to100° C. and stirred for 16 h. The mixture was diluted with EA and washedwith brine. The organic layer was dried with Na₂SO₄ and concentratedunder vacuum. The residue was purified by a FLASH with MeOH:EA=1:15 toafford 450 mg the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=257 [M+1]; 1H-NMR (400 MHz, 6d-DMSO) δppm 7.72 (d, 1H, J=5.6 Hz), 6.41 (s, 2H), 5.71 (d, 1H, J=5.6 Hz),4.91-4.73 (m, 1H), 4.67-4.50 (m, 2H), 4.34 (d, 1H, J=13.0 Hz), 3.69-3.46(m, 5H), 3.30-3.17 (m, 1H), 3.06 (d, 1H, J=11.3 Hz), 1.80-1.54 (m, 2H).

Example B52: Synthesis of2-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol

Step 1: Synthesis of (3S,4R)-tert-butyl3-fluoro-4-(2-hydroxyethoxy)piperidine-1-carboxylate

NaH (1.35 g, 33.9 mmol) was added batchwise to tert-butyl(3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (3.0 g, 13.6 mmol) inDMF (10 mL) at 0° C. The mixture was stirred at 0° C. for 20 min.(2-bromoethoxy)(tert-butyl)dimethylsilane (9.76 g, 40.8 mmol) was addedand the mixture was stirred at rt for 16 h. The mixture was diluted withEA and washed with brine. The organic layer was dried with Na₂SO₄ andconcentrated under vacuum. The residue was purified by a FLASH withPE:EA=10:1 to afford 3.0 g the title compound as a colorless oil.

Step 2: Synthesis of2-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol

TFA (15 mL) was added to tert-butyl(3S,4R)-4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3-fluoropiperidine-1-carboxylate(3.0 g, 7.94 mmol) in DCM (20 mL) at rt. The resulting mixture wasstirred at rt for 1 h. The mixture was concentrated under vacuum and theresidue was mixed with 2-chloropyrimidin-4-amine (873 mg, 6.74 mmol) andDIEA (629 mg, 4.88 mmol) in DMSO (10 mL). The mixture was stirredovernight at 100° C. The mixture was diluted with EA 50 mL and washedwith brine, the organic layer was dried with Na₂SO₄ and concentratedunder vacuum. The residue was purified by a FLASH with MeOH:EA=1:15 toafford 1.1 g the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=257 [M+1]; 1H-NMR (400 MHz, 6d-DMSO) δppm 7.72 (d, 1H, J=5.6 Hz), 6.41 (s, 2H), 5.71 (d, 1H, J=5.6 Hz),4.94-4.69 (m, 1H), 4.67-4.52 (m, 2H), 4.34 (d, 1H, J=13.3 Hz), 3.72-3.45(m, 5H), 3.31-3.19 (m, 1H), 3.07 (t, 1H, J=11.4 Hz), 1.77-1.44 (m, 2H).

Example B53: Synthesis ofrac-cis-tert-butyl-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamateandrac-trans-tert-butyl-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate

Step 1: Synthesis ofrac-1-(tert-butoxycarbonyl)-4-methoxypiperidine-3-carboxylic Acid

A mixture of rac-1-tert-butyl 3-methyl4-methoxypiperidine-1,3-dicarboxylate (3 g, 10.9 mmol), NaOH (871 mg,21.8 mmol) in MeOH (25 mL) and water (10 mL) was stirred at 80° C. for 1h. The mixture was extracted with EA. The organic layer was dried overNa₂SO₄ and concentrated to dryness to afford the title compound (2.7 g,95%) as a light-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=282 [M+23].

Step 2: Synthesis of rac-4-methoxypiperidine-3-carboxylic Acid

To a solution ofrac-1-[(tert-butoxy)carbonyl]-4-methoxypiperidine-3-carboxylic acid (1.5g, 5.78 mmol) in DCM (20 mL) was added TFA (7 mL). The mixture wasstirred at rt for 1 h. The solvent was removed by concentration todryness to afford the title compound (1.5 g, crude) as light-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=160 [M+1].

Step 3: Synthesis ofrac-1-(benzyloxycarbonyl)-4-methoxypiperidine-3-carboxylic Acid

To a solution of rac-4-methoxypiperidine-3-carboxylic acid (1.5 g,crude) and NaOH (931 mg, 23.3 mmol) in water (20 mL) was added CbzCl(1.49 g, 8.74 mmol). After for 1 h, the resulting mixture was washedwith EA. The aqueous layer was acidified with 1N HCl and extracted withEA. The organic layer was dried over Na₂SO₄ and concentrated to drynessto afford the title compound (1.2 g, 70% two steps) as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=294 [M+1].

Step 4: Synthesis of rac-benzyl3-(tert-butoxycarbonylamino)-4-methoxypiperidine-1-carboxylate

To a solution ofrac-1-[(tert-butoxy)carbonyl]-4-methoxypiperidine-3-carboxylic acid (1.2g, 4.09 mmol) and TEA (1.23 g, 12.2 mmol) in tBuOH (40 mL), was addedDPPA (1.49 g, 6.13 mmol). The mixture was stirred at 100° C. for 3 h.The solvent was removed by concentration and the residue was purified onsilica gel column with 60% EtOAc in PE to afford the title compound (300mg) as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=387 [M+23].

Step 5: Synthesis of rac-tert-butyl 4-methoxypiperidin-3-ylcarbamate

A mixture of rac-benzyl3-{[(tert-butoxy)carbonyl]amino}-4-methoxypiperidine-1-carboxylate (300mg, 823 μmol), Pd/C (87.5 mg, 82.3 μmol) in MeOH (20 mL) was stirred atrt for 2 h under H₂ atmosphere. The solid was filtered out and thefiltrate was concentrated to dryness to afford the title compound (100mg) as a colorless oil.

Analytical Data:LC-MS: (ES, m/z)=231 [M+1].

Step 6: Synthesis ofrac-cis-tert-butyl-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamateandrac-trans-tert-butyl-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate

A mixture of rac-tert-butyl N-(4-methoxypiperidin-3-yl)carbamate (100mg, 434 μmop, 2-chloropyrimidin-4-amine (56.2 mg, 434 μmol) and DIEA(168 mg, 1.30 mmol) in DMSO (8 mL) was stirred at 100° C. for 3 h. Theresulting mixture was purified on prep-HPLC to afford peak 2:rac-cis-tert-butyl-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate(18 mg) as an off-white solid and peak 1:rac-trans-tert-butyl-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ylcarbamate(55 mg) as an off-white solid.

Analytical Data: LC-MS: (ES, m/z)=324 [M+1].

Example B54: Synthesis of(3R,4R)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-oland(3S,4S)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol

Step 1: Synthesis of tert-butyl5,5-difluoro-5,6-dihydropyridine-1(2H)-carboxylate

A solution of tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate(355 mg, 1.5 mmol, 1 equiv.) in DCM (6 mL) was added DMAP (274 mg, 2.25mmol, 1.5 equiv.), followed by trifluoromethanesulfonyltrifluoromethanesulfonate (550 mg, 1.95 mmol, 1.3 equiv.) at 0° C. Thereaction was carried on at 0° C. for 1 h before quenching with sat.NaHCO₃ (30 mL). The mixture was extracted with DCM (10 mL*3). Theorganic layer was combined and concentrated. The residue was dissolvedin toluene (5 mL). DBU (569 mg, 3.75 mmol, 2.5 equiv) was added. Thereaction was carried on at 70° C. for 18 h. After cooling down to r.t.,the mixture was diluted with MTBE (50 mL). The mixture was washed withwater (10 mL). The organic layer was combined and concentrated. Theresidue was purified by silica gel column chromatography (PE/EA=10:1) toafford the title compound (260 mg, 79.3%) as a light-yellow oil.

Analytical Data: 1H-NMR (400 MHz, CD₃Cl) δ ppm 6.23-6.17 (m, 1H),5.98-5.92 (m, 1H), 4.06-4.00 (m, 2H), 3.91-3.65 (m, 2H), 1.51 (s, 9H).

Step 2: Synthesis of tert-butylcis-3,3-difluoro-4,5-dihydroxypiperidine-1-carboxylate

A mixture of tert-butyl3,3-difluoro-1,2,3,6-tetrahydropyridine-1-carboxylate (153 mg, 700 μmol,1 equiv.) in acetone (4 mL) and H₂O (1 mL) was added K₂OsO₄.2H₂O (12.8mg, 35 μmol, 0.05 equiv.) and NMO (244 mg, 2.1 mmol, 3 equiv.) at rt.The reaction was carried on at 40° C. for 18 h. After cooling down tort, the mixture was diluted with EA (50 mL), washed with 10% Na₂S₂O₃solution (10 mL) and water (10 mL). The organic layer was concentrated,the residue was purified by silica gel column chromatography(DCM/EA=2:1) to afford the title compound (71 mg, 40.1%) as a whitesolid.

Analytical Data: 1H-NMR (400 MHz, 6d-DMSO) δ ppm 5.88 (d, 1H, J=5.1 Hz),5.18 (d, 1H, J=5.9 Hz), 3.96-3.60 (m, 3H), 3.60-3.44 (m, 1H), 3.34-3.19(m, 1H), 3.10-2.76 (m, 1H), 1.40 (s, 9H).

Step 3: Synthesis of tert-butylcis-3,3-difluoro-5-hydroxy-4-methoxypiperidine-1-carboxylate

A solution of tert-butylcis-3,3-difluoro-4,5-dihydroxypiperidine-1-carboxylate (69.6 mg, 275μmol, 1 equiv.) in THF (2 mL) was added NaH (10.9 mg, 275 μmol, 1equiv., 60%) at 0° C. After 30 min, MeI (39.0 mg, 275 μmol, 1 equiv.)was added. The reaction was carried on at 0° C. for 1 h and at rt for 18h. After quenching with sat. NH₄Cl (10 mL), the mixture was extractedwith EA (5 mL*3). The organic layer was combined and concentrated. Theresidue was purified by silica gel column chromatography (DCM/EA=2:1) toafford the title compound (22 mg, 30%) as a colourless syrup.

Step 4: Synthesis of cis-5,5-difluoro-4-methoxypiperidin-3-ol

A solution of tert-butylcis-3,3-difluoro-5-hydroxy-4-methoxypiperidine-1-carboxylate (240 mg,900 μmol, 1 equiv.) in TFA (1 mL) and DCM (3 mL) was stirred at rt for 3h and concentrated to afford the title compound (220 mg, crude) ascolorless oil.

Analytical Data: LC-MS: (ES, m/z)=168 [M+1].

Step 5: Synthesis ofcis-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol and(3S,4S)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol

220 mg of cis-5,5-difluoro-4-methoxypiperidin-3-ol was dissolved in IPA(2 mL). 2-chloropyrimidin-4-amine (116 mg, 900 μmol, 1 equiv.) wasadded, followed by TEA (454 mg, 4.50 mmol, 5 equiv.). The reaction wascarried on at 100° C. for 18 h. After cooling down to rt, the mixturewas concentrated. The residue was purified by prep-TLC (DCM/MeOH=20:1)to afford(3S,4S)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol(50 mg, 21.36%) as a white solid. The compound was separated byprep-chiral-HPLC with following conditions: CHIRAL Cellulose-SB4.6*100mm 3 um; mobile phase: Hex(0.1% DEA):IPA=70:30; Flow: 1.0 mL/min; toafford peak 1:(3R,4R)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-olor(3S,4S)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol(20 mg) as pale-yellow solid and peak 2:(3R,4R)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-olor(3S,4S)-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol(20 mg) as pale-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=261 [M+1]; 1H-NMR (300 MHz, 3d-CD₃Cl)δ ppm 7.95 (d, 1H, J=5.6 Hz), 5.82 (d, 1H, J=5.6 Hz), 4.87-4.70 (m, 1H),4.67-4.48 (m, 3H), 3.91 (s, 1H), 3.67 (d, 3H, J=1.0 Hz), 3.67-3.60 (m,1H), 3.51 (ddd, 1H, J=29.0, 14.0, 1.8 Hz), 3.12 (dd, 1H, J=12.9, 10.1Hz), 2.41 (s, 1H).

Example B55: Synthesis ofrac-cis-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol

Step 1: Synthesis of rac-cis-tert-butyl3,4-dihydroxy-4-methylpiperidine-1-carboxylate

To a solution of tert-butyl4-methyl-1,2,3,6-tetrahydropyridine-1-carboxylate (300 mg, 1.52 mmol) inTHF (3 mL) and H₂O (1 mL), K₂OsO₄.2H₂O (50.4 mg, 152 umol) and NMO (533mg, 4.56 mmol) were added at rt and stirred for 12 h. The reactionmixture was diluted with sat. Na₂S₂SO₃.aq, and extracted with EA andbrine. The organic layer was dried over Na₂SO₄, filtered and evaporatedto afford the title compound (350 mg, crude) as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=254 [M+23].

Step 2: Synthesis ofrac-cis-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol

To a solution of rac-tert-butylcis-3,4-dihydroxy-4-methylpiperidine-1-carboxylate (350 mg, crude) inDCM (6 mL), TFA (2 mL) was added and stirred at rt for 2 h. The reactionmixture was evaporated and the residue dissolved in IPA (3 mL),2-chloropyrimidin-4-amine (160 mg, 1.23 mmol) and TEA (621 mg, 6.15mmol) was added and the mixture was heated to 100° C. and stirred for 12h. The reaction mixture was diluted with water, extracted with EA andwashed with brine. The organic layer was dried over Na₂SO₄, filtered andevaporated. The residue was purified by column chromatography(DCM:MeOH=20:1) to afford the title compound (200 mg, 72.7%) as a yellowsolid.

Analytical Data: LC-MS: (ES, m/z)=225 [M+1].

Example B56: Synthesis ofrac-trans-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol

Step 1: Synthesis of tert-butyl6-methyl-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylate

To a solution of tert-butyl4-methyl-1,2,3,6-tetrahydropyridine-1-carboxylate (500 mg, 2.53 mmol) inDCM (20 mL) was added m-CPBA (870 mg, 5.06 mmol) and the mixture wasstirred at rt for 2 h. The mixture was extracted with EA and water. Theorganic layer was concentrated and purified by FLASH (30% EA in PE) toafford the title compound of 460 mg as colorless oil.

Analytical Data: LC-MS: (ES, m/z)=214 [M+1].

Step 2: Synthesis of rac-tert-butyltrans-3,4-dihydroxy-4-methylpiperidine-1-carboxylate

To a solution of rac-tert-butyl6-methyl-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (100 mg, 468μmol) in H₂O (5 mL) were added KOH (448 mg, 8.00 mmol) and the solutionwas stirred at 75° C. for 15 h. The mixture was extracted with EA, driedand concentrated to afford the title compound 180 mg as yellow oil.

Analytical Data: LC-MS: (ES, m/z)=232 [M+1].

Step 2: Synthesis ofrac-trans-1-(4-aminopyrimidin-2-yl)-4-methylpiperidine-3,4-diol

To a solution of rac-tert-butyltrans-3,4-dihydroxy-4-methylpiperidine-1-carboxylate (300 mg, 1.29 mmol)in DCM (10 mL) were added TFA (3 mL) and the mixture was stirred for 1.5h at rt. The solvent was removed under reduced pressure. The residue wasdissolved in IPA (2 mL), 2-chloropyrimidin-4-amine (88.8 mg, 686 μmol)and DIEA (441 mg, 3.42 mmol) were added and the solution was heated to120° C. for 10 h. The mixture was extracted with EA and water. Theorganic concentrated and was purified by FLASH (50% MeOH in DCM) toafford the title compound of 80 mg as pale-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=225 [M+1].

Example B57: Synthesis of rac-tert-butyl1-(4-aminopyrimidin-2-yl)-3,3-difluoropiperidin-4-ylcarbamate

The mixture of rac-tert-butyl N-(3,3-difluoropiperidin-4-yl)carbamate(200 mg, 0.85 mmol, 1 equiv.), 2-chloropyrimidin-4-amine (109.67 mg,0.847 mmol, 1 equiv.) and TEA (256.98 mg, 2.540 mmol, 3 equiv.) in IPA(3 mL) was stirred for 3 h at 100° C. The mixture was concentrated andthe residue was applied onto a silica gel column with DCM/MeOH (20:1).This resulted in 100 mg (35.9%) of the title compound as a light-yellowsolid.

Analytical Data: LC-MS: (ES, m/z)=330 [M+1].

Example B58: Synthesis ofrac-cis-1-(5-amino-1,2,4-triazin-3-yl)-3-fluoro-4-methylpiperidin-4-ol

The mixture of 3-chloro-1,2,4-triazin-5-amine (200 mg, 1.53 mmol),cis-3-fluoro-4-methylpiperidin-4-ol (243 mg, 1.83 mmol) and TEA (309 mg,3.06 mmol) in IPA (5 mL) was stirred at 100° C. for 2 h. Water was addedand the reaction was extracted with EA. The organic layer was purifiedby Prep-TLC (DCM:MeOH=10:1). This result in 300 mg (34.4%) the titlecompound as grey solid.

Analytical Data: LC-MS: (ES, m/z)=228 [M+1].

Example B59: Synthesis of2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amineand2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amineand2-((3R,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amineand2-((3S,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine

Step 1: Synthesis of rac-tert-butyl3-fluoro-4-methoxy-3-methylpiperidine-1-carboxylate

Rac-tert-butyl 3-fluoro-4-hydroxy-3-methylpiperidine-1-carboxylate (Step3, Example B1; 4 g, 17 mmol) was dissolved in DMF (40 mL), sodiumhydride (820 mg, 34.2 mmol) was added at 0° C. The mixture was stirredat rt for 1 h. Iodomethane (4.82 g, 34.2 mmol) was added and thereaction was stirred at rt for another 2 h. The reaction was quenchedwith water/ice, extracted with EA, washed with brine, dried overanhydrous sodium sulfate and concentrated under vacuum to afford 5.1 gof tert-butyl 3-fluoro-4-methoxy-3-methylpiperidine-1-carboxylate ascolorless oil.

Step 2: Synthesis ofrac-2-(3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine

Rac-tert-butyl 3-fluoro-4-methoxy-3-methylpiperidine-1-carboxylate (5.1g) was dissolved in HCl/dioxane (4M, 50 mL). The reaction was stirred atrt for 2 h. The mixture was concentrated under vacuum. The residue wasmixed with 2-chloropyrimidin-4-(4.21 g, 32.5 mmol) and TEA (5.47 g, 54.2mmol) in IPA (30 mL). The mixture was stirred at 100° C. and stirred for16 h. The reaction was concentrated under vacuum and the residue waspurified by FLASH (DCM:MeOH=10:1). This resulted in 1.6 g of the titlecompound as a white solid, which was further separated to four isomersusing following conditions:

Analytical Data: LC-MS: (ES, m/z)=241 [M+1].

Column name: CHIRAL ND(2) 4.6*100 mm, 3 um; Co-Solvent: MeOH (0.1% DEA);Gradient (B %): 10% to 50% in 4.0 min, hold 2.0 min at 50%; Flow(mL/min) to afford2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amineor2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine(490 mg) and2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amineor 2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine (440mg). Both are pale-yellow solids.

Column name: CHIRAL ND(2) 4.6*100 mm, 3 um; Co-Solvent: MeOH (0.1% DEA);Gradient (B %): 10% to 50% in 4.0 min, hold 2.0 min at 50%; Flow(mL/min) to afford2-((3R,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amineor2-((3S,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine(81 mg) and2-((3S,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amineor2-((3R,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-amine(123 mg). Both are pale-yellow solids.

Example B60: Synthesis of rac-tert-butyl2-(azetidin-3-yl)-2-(methylsulfonyl)ethylcarbamate

Step 1: Synthesis of rac-benzyl3-(1-(methylsulfonyl)prop-2-ynyl)azetidine-1-carboxylate

Cs₂CO₃ (544 mg, 1.67 mmol) was added to 2-methanesulfonylacetonitrile (1g, 8.39 mmol) and benzyl 3-iodoazetidine-1-carboxylate (3.96 g, 12.5mmol) in DMF (5 mL) at rt. The resulting mixture was stirred for 8 h at80° C. The mixture was diluted with EA and washed with brine. Theorganic layer was dried with Na₂SO₄ and concentrated under vacuum. Theresidue was purified by a silica gel column with PE:EA=5:1 to afford 1.2g the title compound as a colorless oil.

Analytical Data:LC-MS: (ES, m/z)=308 [M+1].

Step 2: Synthesis of rac-Benzyl3-(2-amino-1-(methylsulfonyl)ethyl)azetidine-1-carboxylate

Rac-Benzyl 3-[cyano(methanesulfonyl)methyl]azetidine-1-carboxylate (1.2g, 3.89 mmol) and Raney-Ni (10 mg) in EtOH (4 mL) were stirred for 8 hunder H2 atmosphere at rt. The solid was filtered out, filtrate wasconcentrated under reduced pressure to give 600 mg the title compound ascolorless oil.

Analytical Data: LC-MS: (ES, m/z)=313 [M+1].

Step 3: Synthesis of rac-benzyl3-(2-(tert-butoxycarbonylamino)-1-(methylsulfonyl)ethyl)azetidine-1-carboxylate

(Boc)₂O (829 mg, 3.84 mmol) was added to Na₂CO₃ (407 mg, 3.84 mmol)rac-benzyl 3-(2-amino-1-methanesulfonylethyl)azetidine-1-carboxylate(600 mg, 1.92 mmol) in dioxane/H₂O (10 mL/3 mL) at 0° C. The resultingmixture was stirred at rt for 16 h. The mixture was diluted with EA andwashed with brine. the organic layer was dried with Na₂SO₄ andconcentrated under vacuum. The residue was purified by a silica gelcolumn with PE:EA=5:1 to afford 650 mg the title compound as a colorlessoil.

Analytical Data: LC-MS: (ES, m/z)=413 [M+1].

Step 4: Synthesis of rac-tert-butyl2-(azetidin-3-yl)-2-(methylsulfonyl)ethylcarbamate

The mixture ofrac-benzyl-3-(2-amino-1-methanesulfonylethyl)azetidine-1-carboxylate(600 mg, 1.92 mmol) and Pd(OH)₂/C (300 mg, 2.14 mmol) in MeOH (50 mL)was stirred overnight under an atmosphere of hydrogen at rt. The solidwas filtered out, filtrate was concentrated under reduced pressure togive the title compound (300 mg) as colorless oil.

Analytical Data: LC-MS: (ES, m/z)=279 [M+1].

Example B61: Synthesis ofrac-cis-2-(hexahydrofuro[3,4-b]pyrrol-1-yl)pyrimidin-4-amine

The mixture of 2-chloropyrimidin-4-amine (370 mg, 2.85 mmol),rac-cis-hexahydro-1H-furo[3,4-b]pyrrole (322 mg, 2.85 mmol) and DIPEA(1.10 g, 8.55 mmol) in DMSO (8 mL) was stirred for 12 h at 120° C. Thereaction mixture was diluted with water, extracted with EA and washedwith brine. The organic layer was dried over Na₂SO₄, filtered,evaporated and purified by column chromatography (DCM:MeOH=20:1) toafford the title compound (410 mg, 69.8%) as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=207 [M+1].

Example B62: Synthesis of tert-butyl(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methylcarbamate

Step 1: Synthesis of 1-tert-butyl 4-methyl4-methoxypiperidine-1,4-dicarboxylate

To a solution of 1-tert-butyl 4-methyl4-hydroxypiperidine-1,4-dicarboxylate (1.5 g, 5.78 mmol) in THF (40 mL)was added NaH (346 mg, 8.67 mmol) at 0° C. After 10 min, MeI (1.23 g,8.67 mmol) was added and stirred for 2 h. The mixture was quenched withice-water and extracted with EA. The organic layer was dried over Na₂SO₄and concentrated to dryness. The residue was purified on silica gelcolumn with 10% EA in PE to afford 1-tert-butyl 4-methyl4-methoxypiperidine-1,4-dicarboxylate (1.3 g) as a light-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=296 [M+23].

Step 2: Synthesis of 1-benzyl 4-methyl4-methoxypiperidine-1,4-dicarboxylate

To a solution of 1-tert-butyl 4-methyl4-methoxypiperidine-1,4-dicarboxylate (1.3 g, 4.75 mmol) in DCM (20 mL)was added TFA (8 mL). The mixture was stirred for 1 h at rt. Thereaction was concentrated. The reside was dissolved in dioxane (20 mL)and water (10 mL), K₂CO₃ (1.94 g, 14.1 mmol) and CbzCl (1.60 g, 9.42mmol) was added at rt and stirred for 2 h. The reaction was extractedwith EA, dried over Na₂SO₄ and concentrated to dryness to afford thetitle compound (1.2 g) as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=309 [M+1].

Step 3: Synthesis of1-(benzyloxycarbonyl)-4-methoxypiperidine-4-carboxylic Acid

To a mixture of 1-benzyl 4-methyl 4-methoxypiperidine-1,4-dicarboxylate(1.1 g, 3.57 mmol) in MeOH (20 mL) and water (5 mL) was added NaOH (285mg, 7.14 mmol). The mixture was stirred at 70° C. for 2 h. After coolingto rt, the pH was adjusted to 5 with 1N HCl and extracted with EA. Theorganic layer was dried over Na₂SO₄, filtered and concentrated todryness to afford the title compound (1 g) as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=294 [M+1].

Step 4: Synthesis of Benzyl4-carbamoyl-4-methoxypiperidine-1-carboxylate

The mixture of 1-[(benzyloxy)carbonyl]-4-methoxypiperidine-4-carboxylicacid (950 mg, 3.23 mmol), DIEA (834 mg, 6.46 mmol), ammonia (1.82 g,37.4 mmol) and HATU (1.84 g, 4.84 mmol) in DCM (20 mL) was stirred for 2h at rt. The organic layer was separated and washed with water, driedover Na₂SO₄, filtered and concentrated to dryness. The residue waspurified on silica gel column with 60% EtOAc in PE to afford the titlecompound (900 mg) as colorless oil.

Analytical Data: LC-MS: (ES, m/z)=293 [M+1].

Step 5: Synthesis of Benzyl4-(aminomethyl)-4-methoxypiperidine-1-carboxylate

To a solution of benzyl 4-carbamoyl-4-methoxypiperidine-1-carboxylate(600 mg, 2.05 mmol) in THF (20 mL) was added NaBH₄ (310 mg, 8.20 mmol),followed by BF₃.Et₂O (1.16 g, 8.20 mmol) at rt. The mixture was stirredfor 2 h at rt. Water was added and the mixture was extracted with EA.The organic layer was dried over Na₂SO₄, filtered and concentrated todryness to afford the title compound (1.4 g, crude) as colorless oil.

Analytical Data: LC-MS: (ES, m/z)=279 [M+1].

Step 6: Synthesis of benzyl4-((tert-butoxycarbonylamino)methyl)-4-methoxypiperidine-1-carboxylate

The solution of benzyl 4-(aminomethyl)-4-methoxypiperidine-1-carboxylate(1.4 g, crude) and Boc₂O (1.21 g, 5.58 mmol) in DCM (20 mL) was stirredat rt for 1 h. Water was added and the organic layer was separated andpurified on silica gel column with 60% EA in PE to afford the titlecompound (250 mg) as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=401 [M+23].

Step 7: Synthesis of Tert-butyl (4-methoxypiperidin-4-yl)methylcarbamate

A mixture of benzyl4-({[(tert-butoxy)carbonyl]amino}methyl)-4-methoxypiperidine-1-carboxylate(240 mg, 634 μmol) and Pd/C (100 mg, 95.1 μmol) in MeOH (20 mL) wasstirred at rt for 1 h under a H2 atm. The solid was filtered out. Thefiltrate was concentrated to dryness to afford the title compound (130mg) as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=245 [M+1].

Step 8: Synthesis of tert-butyl(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)methylcarbamate

A mixture of 1-(4-methoxypiperidin-4-yl)methanamine (120 mg, 832 μmop,2-chloropyrimidin-4-amine (107 mg, 832 μmol) and TEA (167 mg, 1.66 mmol)in iPrOH (20 mL) was stirred at 80° C. for 2 h. The mixture wasconcentrated and the residue was purified on prep-TLC (EtOAc:PE=1:1) toafford the title compound (95 mg) as an off-white solid.

Analytical Data: LC-MS: (ES, m/z)=338 [M+1].

Example B63: Synthesis of2-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-yloxy)ethanol

HCl (6M, 5 mL) was added to2-[(3S,4R)-4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3-fluoro-3-methylpiperidin-1-yl]-4-(2,2,12,12-tetramethyl-5,9-dioxa-7-aza-2,12-disilatridecan-7-yl)pyrimidine(600 mg, 930 μmol, from Step 2 of Example B70) in EtOH (5 mL). Themixture was stirred at 80° C. for 1 h. The mixture was concentratedunder vacuum to afford 200 mg the title compound as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=271 [M+1].

Example B64: Synthesis of tert-butyl2-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)ethylcarbamate

Step 1: Synthesis of benzyl4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate

To a solution of ACN (1.73 g, 42.1 mmol) in THF (80 mL) was added n-Buli(23.5 mL, 58.9 mmol, 2.5 M) at −78° C. The mixture was stirred at −78°C. for 30 min. Then a solution of benzyl 4-oxopiperidine-1-carboxylate(10.3 g, 44.2 mmol) in THF (20 mL) was added. The mixture was stirred atrt for 2 h. The mixture was quenched with H₂O (30 mL) and extracted withEA and washed with brine. The organic layer was dried with Na₂SO₄ andconcentrated under vacuum. The residue was purified by Flash ColumnSilica-CS (PE:EA=10:1 to 3:2). This resulted in 1 g (90.9%) of the titlecompound as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=275 [M+1].

Step 2: synthesis of benzyl4-(cyanomethyl)-4-methoxypiperidine-1-carboxylate

To a solution of benzyl4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate (250 mg, 911 μmol) andiodomethane (283 mg, 2 mmol) in DMF (30 mL) was added NaH (216 mg, 5.45mmol) at 0° C. Then the mixture was stirred at rt for 13 h. The mixturewas quenched with H₂O (4 mL) and extracted with EA and washed withbrine. The organic layer was dried with Na₂SO₄ and concentrated undervacuum. The residue was purified by Flash Column Silica-CS (PE:EA=1:1).This resulted in 940 mg of benzyl4-(cyanomethyl)-4-methoxypiperidine-1-carboxylate as a light-yellow gum.

Analytical Data: LC-MS: (ES, m/z)=311 [M+23].

Step 3: Synthesis of Benzyl4-(2-aminoethyl)-4-methoxypiperidine-1-carboxylate

To a solution of benzyl4-(cyanomethyl)-4-methoxypiperidine-1-carboxylate (840 mg, 2.91 mmol) inTHF (30 mL) was added BH₃-THF (8.73 mL, 8.73 mmol, 1M) at 0° C. Then themixture was stirred at rt for 5 h. The reaction was quenched with MeOH(8 mL) and concentrated to give the crude the title compound (900 mg).

Analytical Data: LC-MS: (ES, m/z)=293 [M+1].

Step 4: Synthesis of benzyl4-(2-(tert-butoxycarbonylamino)ethyl)-4-methoxypiperidine-1-carboxylate

To a solution of benzyl4-(2-aminoethyl)-4-methoxypiperidine-1-carboxylate (850 mg, 2.90 mmol)in DCM (30 mL) was added TEA (586 mg, 5.80 mmol) and di-tert-butyldicarbonate (949 mg, 4.35 mmol). Then the mixture was stirred at rt for10 h. The mixture was extracted with EA and washed with brine. Theorganic layer was dried and concentrated under vacuum. The residue waspurified by Flash Column Silica-CS (PE:EA=10:1 to 3:2). This resulted in900 mg (79.6%) of the title compound as a light-yellow gum.

Analytical Data: LC-MS: (ES, m/z)=415 [M+23].

Step 5: Synthesis of tert-butyl2-(4-methoxypiperidin-4-yl)ethylcarbamate

To a solution of benzyl4-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4-methoxypiperidine-1-carboxylate(420 mg, 1.07 mmol) in MeOH (25 mL) was added Pd/C (200 mg). Then themixture was hydrogenated under hydrogen balloon at rt for 2 h. Thereaction mixture was filtered through celite bed, washed with MeOH (100mL) and the filtrate was concentrated to afford a crude product (250 mg)the title compound, which was used directly for the next step.

Analytical Data: LC-MS: (ES, m/z)=259 [M+1].

Step 6: synthesis of tert-butyl2-(1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-4-yl)ethylcarbamate

To a solution of tert-butylN4-[2-(4-methoxypiperidin-4-yl)ethyl]carbamate (260 mg, 1 mmol) in IPA(16 mL), was added 2-chloropyrimidin-4-amine (116 mg, 900 μmol) andDIPEA (323 mg, 2.50 mmol). The mixture was stirred at 120° C. for 13 h.The mixture was extracted with EA and washed with brine. The organiclayer was dried and concentrated under vacuum. The residue was purifiedby prep.TLC (DCM:MeOH=10:1). This resulted in 280 mg (79.7%) of thetitle compound as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=352 [M+1].

Example B65: Synthesis of1-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol

Step 1: Synthesis of (3R,4S)-tert-butyl3-fluoro-4-(2-hydroxy-2-methylpropoxy)piperidine-1-carboxylate

NaH (175.12 mg, 7.297 mmol, 8 equiv.) was added to the mixture oftert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (200 mg,0.912 mmol, 1 equiv.) and 2,2-dimethyloxirane (526.19 mg, 7.297 mmol, 8equiv.) in DMF (5 mL) at 0° C. The resulting solution was stirredovernight at rt. The reaction was quenched by the addition of 10 mL ofwater. The resulting solution was extracted with EA, washed with brineand concentrate to afford 100 mg (37.63%) of the title compound aslight-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=292 [M+1].

Step 2: Synthesis of1-((3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol

Tert-butyl(3R,4S)-3-fluoro-4-(2-hydroxy-2-methylpropoxy)piperidine-1-carboxylate(100.00 mg, 0.343 mmol) was added to the solution of TFA (1 mL) in DCM(3 mL). The resulting solution was stirred for 2 hr at rt. The resultingmixture was concentrated under vacuum and the residue was mixed with2-chloropyrimidin-4-amine (50 mg, 0.386 mmol, 1 equiv.) and TEA (117.16mg, 1.158 mmol, 3 equiv.) in IPA (2 mL). The resulting solution wasstirred for 12 h at 100° C. The mixture was concentrated under vacuumand the residue was applied onto a silica gel column with DCM/MeOH(15:1). This resulted in 20 mg (18.22%) of the title compound aslight-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=285 [M+1].

Example B66: Synthesis of1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol

Step 1: Synthesis of (3S,4R)-tert-butyl3-fluoro-4-(2-hydroxy-2-methylpropoxy)piperidine-1-carboxylate

NaH (262.68 mg, 10.946 mmol, 6 equiv.) was added to the solution oftert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (400.00mg, 1.824 mmol, 1 equiv.) and 2,2-dimethyloxirane (1315.49 mg, 18.244mmol, 10 equiv.) in DMF (20.00 mL). The resulting solution was stirredfor overnight at rt. The reaction was then quenched by the addition of 3mL of water. The resulting solution was extracted with EA andconcentrated under vacuum. This resulted in 200 mg (37.63%) of the titlecompound as yellow oil.

Analytical Data: LC-MS: (ES, m/z)=292 [M+1].

Step 2: Synthesis of1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)-2-methylpropan-2-ol

Tert-butyl (3S,4R)-3-fluoro-4-(2-hydroxy-2-methylpropoxy)piperidine-1-carboxylate(200.00 mg, 0.686 mmol, 1 equiv.) was added to DCM/TFA (8.00 mL/4.00mL). The resulting solution was stirred for 2 h at rt. The resultingmixture was concentrated under vacuum. The residue was mixed with2-chloropyrimidin-4-amine (67.74 mg, 0.523 mmol, 1 equiv.) and TEA(158.73 mg, 1.569 mmol, 3.0 equiv.) in IPA (3 mL) at 100° C. and stirredfor 3 h. The solvent was removed and the residue was applied onto asilica gel column with DCM/MeOH (15:1). This resulted in 55 mg (37%) ofthe title compound as light-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=285 [M+1].

Example B67: Synthesis of2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-amine

Step 1: Synthesis of tert-butyl(3R,4S)-3-fluoro-4-(methoxy-d3)piperidine-1-carboxylate

NaH (218 mg, 9.08 mmol) was added to tert-butyl(3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (1000 mg, 4.56 mmol)in DMF (20 mL, 22.6 mmol) at 0° C. After stirring for 20 minutes, CD₃I(3.30 g, 22.8 mmol) was added and the solution was stirred at rt for 16h. The reaction was quenched by the addition of 5 mL of water. Thesolids were filtered out. The resulting solution was extracted with EAand washed with brine and concentrated. This is resulted 1140 mg of thetitle compound as a light-yellow oil.

Step 2: Synthesis of2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-amine

TFA (2 mL) was added to tert-butyl(3R,4S)-3-fluoro-4-(methoxy-d3)piperidine-1-carboxylate (1140 mg, 4.82mmol) in DCM (6 mL) and the solution was stirred for 2 h at rt. Themixture was concentrated under vacuum and residue was dissolved in IPA(20 mL), followed by 2-chloropyrimidin-4- (496 mg, 3.83 mmol) and TEA(0.6 mL). The mixture was stirred overnight at 100° C. The mixture wasconcentrated and the residue was purified by FLASH (5% MeOH in EA) toafford 425 mg of the title compound as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=230 [M+1].

Example B68: Synthesis of2-((3R,4S)-4-cyclopropoxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine

Step 1: Synthesis of (3R,4S)-tert-butyl3-fluoro-4-(vinyloxy)piperidine-1-carboxylate

A mixture of tert-butyl(3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (263 mg, 1.2 mmol, 1equiv.), ethenyl acetate (515 mg, 5.99 mmol, 5 equiv.), Ir(COD)₂Cl₂(80.3 mg, 120 μmol, 0.1 equiv.) and Na₂CO₃ (127 mg, 1.20 mmol, 1 equiv.)in toluene (1.5 mL) was heated to 100° C. for 3 h. After cooling down tort, the mixture was filtered. The filtrate was concentrated. The residuewas purified by prep-TLC (PE/EA=4:1) to afford the title compound (200mg, 68%) as a colourless syrup.

Step 2: Synthesis of2-((3R,4S)-4-cyclopropoxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine

A solution of diiodomethane (1.17 g, 4.39 mmol, 5.5 equiv.) in DCM (2mL) was added diethylzinc (3.59 mL, 3.59 mmol, 4.5 equiv., 1M inheptane) at 0° C. The mixture was stirred at 0° C. for 1 h. A solutionof tert-butyl (3R,4S)-4-(ethenyloxy)-3-fluoropiperidine-1-carboxylate(196 mg, 800 μmol, 1 equiv.) in DCM (2 mL) was added. The reaction wascarried on at rt for 2 h then concentrated. The residue was suspended inTFA (1 mL) and DCM (3 mL) and stirred for 2 h at rt. The mixture wasconcentrated. The residue was added TEA (404 mg, 4.00 mmol, 5 equiv.),2-chloropyrimidin-4-amine (72.5 mg, 560 μmol, 0.7 equiv.) and IPA (2mL). The mixture was heated to 100° C. for 18 h. After cooling down tort, the mixture was concentrated. The residue was purified by prep-TLC(DCM/MeOH=25:1) to afford2-[(3R,4S)-4-cyclopropoxy-3-fluoropiperidin-1-yl]pyrimidin-4-amine (80mg, 40%) as a white solid.

Analytical Data: 1H-NMR (400 MHz, 3d-CD₃Cl) δ ppm 7.94 (d, 1H, J=5.6Hz), 5.78 (d, 1H, J=5.6 Hz), 4.83 (ddt, 1H, J=48.3, 5.7, 2.7 Hz),4.68-4.59 (m, 1H), 4.58 (s, 2H), 4.32 (dddd, 1H, J=13.4, 5.7, 4.0, 1.5Hz), 3.84-3.71 (m, 1H), 3.61-3.42 (m, 2H), 3.35 (dddd, 1H, J=13.2, 9.3,3.6, 1.7 Hz), 2.05-1.91 (m, 1H), 1.89-1.74 (m, 1H), 0.72-0.63 (m, 2H),0.58-0.49 (m, 2H).

Example B69: Synthesis ofrac-2-(1-(4-aminopyrimidin-2-yl)-3,3-difluoropiperidin-4-yloxy)ethanol

Step 1: Synthesis of rac-tert-butyl4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,3-difluoropiperidine-1-carboxylate

To a solution of rac-tert-butyl3,3-difluoro-4-hydroxypiperidine-1-carboxylate (3 g, 12.6 mmol) in DMF(20 mL) was added NaH (1.25 g, 31.5 mmol, 60%) at 0° C. The mixture wasstirred at 0° C. for 0.5 h. Then(2-bromoethoxy)(tert-butyl)dimethylsilane (9.04 g, 37.8 mmol) was added.The mixture was stirred at rt for 13 h. The mixture was extracted withEA and washed with brine. The organic layer was dried and concentratedunder vacuum. The residue was purified by Flash Column Silica-CS(PE:EA=1:0 to 10:1). This resulted in 3.8 g (76.3%) of the titlecompound as a yellow oil.

Step 2: Synthesis ofrac-2-(1-(4-aminopyrimidin-2-yl)-3,3-difluoropiperidin-4-yloxy)ethanol

To a solution of rac-tert-butyl4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3,3-difluoropiperidine-1-carboxylate(3.7 g, 9.35 mmol) in DCM (10 mL), was added HCl/dioxane (20 mL) at 0°C. Then the mixture was stirred at rt for 2 h. The reaction wasconcentrated and the residue was dissolved in IPA (4 mL), followed byTEA (278 mg, 2.75 mmol) and 2-chloropyrimidin-4-amine (84.7 mg, 654μmol). The mixture was stirred at 120° C. for 13 h. The mixture wasextracted with EA and washed with brine. The organic layer was dried andconcentrated under vacuum. The residue was purified by Flash ColumnSilica-CS (DCM:MeOH=10:1). This resulted in 2 g (79.6%) of the titlecompound as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=275 [M+1].

Example B70: Synthesis of2-((3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl)pyrimidin-4-amine

Step 1: Synthesis of2-((3S,4R)-4-(tert-butyldimethylsilyloxy)-3-fluoro-3-methylpiperidin-1-yl)pyrimidin-4-amine:

Tert-butyl(chloro)dimethylsilane (5.98 g, 39.7 mmol) was added batchwiseto 1H-imidazole (3.60 g, 53.0 mmol) and chirally pure (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (fromExample B1, Step 7, 6.0 g, 26.5 mmol) in DMF at 0° C. The mixture wasstirred at rt for 16 h. The mixture was diluted with EA (500 mL) andwashed with brine, the organic layer was dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by a flash withPE:EA=2:1 to afford 7.5 g the title compound as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=341 [M+1].

Step 2: Synthesis of2-((3S,4R)-4-(tert-butyldimethylsilyloxy)-3-fluoro-3-methylpiperidin-1-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine

The mixture of [2-(chloromethoxy)ethyl]trimethylsilane (11.0 g, 66.0mmol), DIEA (8.51 g, 66 mmol) and2-[(3S,4R)-4-[(tert-butyldimethylsilyl)oxy]-3-fluoro-3-methylpiperidin-1-yl]pyrimidin-4-amine(7.5 g, 22.0 mmol) in DCM (200 mL) was stirred 3 h in reflux. Themixture was diluted with EA (100 mL) and washed with brine. The organiclayer was dried over Na₂SO₄ and concentrated under vacuum. The residuewas purified by a flash with PE:EA=5:1 to afford 10.0 g the titlecompound as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=601 [M+1].

Step 3: Synthesis of (3S,4R)-1-(4-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol

TBAF (83 mL, 83 mmol) was added to2-[(3S,4R)-4-[(tert-butyldimethylsilyl)oxy]-3-fluoro-3-methylpiperidin-1-yl]-4-(2,2,12,12-tetramethyl-5,9-dioxa-7-aza-2,12-disilatridecan-7-yl)pyrimidine(10.0 g, 16.6 mmol) in THF. The mixture was stirred at rt for 2 h. Themixture was concentrated under vacuum. The residue was purified by aPre-TLC with PE:EA=4:1 to afford 6.5 g the title compound as a colorlessoil.

Analytical Data: LC-MS: (ES, m/z)=487 [M+1].

Step 4: Synthesis of2-((3S,4R)-4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-fluoro-3-methylpiperidin-1-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine

NaH (310 mg, 7.75 mmol) was added to2-[(3S,4R)-4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3-fluoro-3-methylpiperidin-1-yl]-4-(2,2,12,12-tetramethyl-5,9-dioxa-7-aza-2,12-disilatridecan-7-yl)pyrimidine(2 g, 3.10 mmol) in DMF at 0° C. The mixture was stirred at 0° C. for 10min. (2-bromoethoxy)(tert-butyl)dimethylsilane (2.22 g, 9.30 mmol) wasadded to the mixture and the resulting solution was stirred at rt for 16h. The mixture was diluted with EA (100 mL) and washed with brine. Theorganic layer was dried and concentrated under vacuum. The residue waspurified by a silica gel column with PE:EA=5:1 to afford 2.1 g the titlecompound as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=645 [M+1].

Step 5: Synthesis of2-((3S,4R)-1-(4-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-yloxy)ethanol

TBAF (10 mL, 10 mmol) was added to2-[(3S,4R)-4-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-3-fluoro-3-methylpiperidin-1-yl]-4-(2,2,12,12-tetramethyl-5,9-dioxa-7-aza-2,12-disilatridecan-7-yl)pyrimidine(600 mg, 930 μmol) in THF (10 mL) at rt. The mixture was stirred inreflux for 1 h. The mixture was concentrated under vacuum. The residuewas purified by a silica gel column with PE:EA=2:1. The result in 200 mgthe title compound as a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=531 [M+1].

Step 6: Synthesis of 2-((3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine

(E)-N-{[(propan-2-yloxy)carbonyl]imino}(propan-2-yloxy)formamide (456mg, 2.26 mmol) was added dropwise to the mixture of PPh₃ (885 mg, 3.38mmol), {[azido(phenoxy)phosphoryl]oxy}benzene (930 mg, 3.38 mmol) and2-{[3S,4R)-3-fluoro-3-methyl-1-[4-(2,2,12,12-tetramethyl-5,9-dioxa-7-aza-2,12-disilatridecan-7-yl)pyrimidin-2-yl]piperidin-4-yl]oxy}ethan-1-ol(600 mg, 1.13 mmol) in THF at 0° C. The mixture was stirred at rt for 16h. The mixture was diluted with EA (100 mL) and washed with brine. Theorganic layer was dried and concentrated under vacuum. The residue waspurified by a Prep-TLC with PE:EA=5:1 to afford 280 mg the titlecompound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=556 [M+1].

Step 7: Synthesis of 2-((3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl)pyrimidin-4-amine

HCl (6M, 5 mL) was added to2-[(3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl]-4-(2,2,12,12-tetramethyl-5,9-dioxa-7-aza-2,12-disilatridecan-7-yl)pyrimidine(260 mg, 467 μmol) in EtOH at rt. The mixture was stirred in reflux for1 h. The mixture was concentrated under vacuum to afford 120 mg2-[(3S,4R)-4-(2-azidoethoxy)-3-fluoro-3-methylpiperidin-1-yl]pyrimidin-4-amineas a colorless oil.

Analytical Data: LC-MS: (ES, m/z)=296 [M+1].

Example B71: Synthesis of1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)propan-2-ol

Step 1: Synthesis of (3S,4R)-tert-butyl3-fluoro-4-(oxiran-2-ylmethoxy)piperidine-1-carboxylate

To a solution of tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (500 mg, 2.28 mmol) inDMF at 0° C. was added NaH (109 mg, 4.56 mmol) and the mixture wasstirred for 20 min at 0° C. Then 2-(bromomethyl)oxirane (936 mg, 6.84mmol) was added into the mixture. The resulting mixture was stirred atrt for 2 h. The mixture was extracted by EA and water. The organic layerwas combined and was dried by Na₂SO₄. The organic layer was concentratedand the crude product was used 600 mg (95%) of the title compound as abrown solid.

Analytical Data: LC-MS: (ES, m/z)=220 [M+1-56].

Step 2: Synthesis of (3S,4R)-tert-butyl3-fluoro-4-(2-hydroxypropoxy)piperidine-1-carboxylate

To a solution of tert-butyl(3S,4R)-3-fluoro-4-[(oxiran-2-yl)methoxy]piperidine-1-carboxylate (750mg, 2.72 mmol) in THF was added LiBHEt₃ (1 M in THF solution) at 0° C.under N₂ atmosphere. The mixture was stirred for 2 h at rt. The mixturewas extracted by EA and water. The organic layer was combined and driedby Na₂SO₄. The organic layer was concentrated to afford 600 mg (80%) ofthe title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=222 [M+1-56].

Step 3: Synthesis of1-((3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)propan-2-ol

To a solution of tert-butyl(3S,4R)-3-fluoro-4-(2-hydroxypropoxy)piperidine-1-carboxylate (600 mg,2.16 mmol) in DCM was added HCl (4 M in dioxane solution) at rt. Themixture was stirred for 2 h at rt. The resulting mixture wasconcentrated under vacuum. The residue was dissolved in DMSO (3 mL),followed by 2-chloropyrimidin-4-amine (380 mg, 2.93 mmol) and DIEA (1.13g, 8.79 mmol). The mixture was stirred for 2 h at 120° C. The mixturewas extracted by EA and water. The organic layer was combined and driedby Na₂SO₄. The organic layer was concentrated and the residue waspurified by Prep-TLC with DCM/MeOH (15:1). This resulted in 210 mg ofthe title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=271 [M+1].

Example B72: Synthesis of2-((3S,4R)-4-cyclopropoxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine

Step 1: Synthesis of (3S,4R)-tert-butyl3-fluoro-4-(vinyloxy)piperidine-1-carboxylate

A mixture of tert-butyl(3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (263 mg, 1.2 mmol, 1equiv.), ethenyl acetate (515 mg, 5.99 mmol, 5 equiv.), Ir(COD)₂Cl₂(80.3 mg, 120 μmol, 0.1 equiv.) and Na₂CO₃ (127 mg, 1.20 mmol, 1 equiv.)in toluene (1.5 mL) was heated to 100° C. for 3 h. After cooling down tort, the mixture was filtered. The filtrate was concentrated. The residuewas purified by prep-TLC (PE/EA=4:1) to afford the title compound (200mg, 68%) as a colourless syrup.

Step 2: Synthesis of2-((3S,4R)-4-cyclopropoxy-3-fluoropiperidin-1-yl)pyrimidin-4-amine

A solution of diiodomethane (1.17 g, 4.39 mmol, 5.5 equiv.) in DCM (2mL) was added diethylzinc (3.59 mL, 3.59 mmol, 4.5 equiv., 1M inheptane) at 0° C. The mixture was stirred at 0° C. for 1 h. A solutionof tert-butyl (3S,4R)-4-(ethenyloxy)-3-fluoropiperidine-1-carboxylate(196 mg, 800 μmol, 1 equiv.) in DCM (2 mL) was added. The reaction wascarried on at rt for 2 h then concentrated. The residue was suspended inTFA (1 mL) and DCM (3 mL) and stirred for 2 h at rt. The mixture wasconcentrated. The residue was added triethylamine (404 mg, 4.00 mmol, 5equiv.), 2-chloropyrimidin-4-amine (72.5 mg, 560 μmol, 0.7 equiv.) andIPA (2 mL). The mixture was heated to 100° C. for 18 h. After coolingdown to rt, the mixture was concentrated. The residue was purified byprep-TLC (DCM/MeOH=25:1) to afford the title compound (80 mg, 40%) as awhite solid.

Analytical Data: 1H-NMR (400 MHz, 3d-CD₃Cl) δ ppm 7.94 (d, 1H, J=5.6Hz), 5.78 (d, 1H, J=5.6 Hz), 4.84 (ddd, 1H, J=48.1, 5.8, 2.8 Hz),4.66-4.59 (m, 1H), 4.57 (s, 2H), 4.39-4.27 (m, 1H), 3.85-3.69 (m, 1H),3.62-3.43 (m, 2H), 3.35 (dddd, 1H, J=13.3, 9.4, 3.6, 1.7 Hz), 1.98(dddd, 1H, J=13.4, 6.8, 5.4, 3.2 Hz), 1.83 (ddd, 1H, J=9.6, 7.8, 4.6Hz), 0.72-0.64 (m, 2H), 0.57-0.47 (m, 2H).

Example B73: Synthesis of3-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)-1,2,4-triazin-5-amine

The solution of (3S,4R)-3-fluoro-4-methoxypiperidine (60 mg, 450 umol,from step 2 of Example B33), DIPEA (174 mg, 1.35 mmol) and3-chloro-1,2,4-triazin-5-amine (64.6 mg, 495 umol, from step 2 ofExample B30) in DMSO (2 mL) was stirred for 2 h at 120° C. The mixturewas extracted by EA and water. The organic layer was dried, concentratedand the residue was purified by Prep-TLC with PE/EA (5:1). This resultedin 40 mg (39%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=228 [M+1].

Example B74: Synthesis of rac-(allcis)-1-(4-aminopyrimidin-2-yl)-5-fluoro-4-methoxypiperidin-3-ol

Step 1: Synthesis ofrac-trans-6-(hydroxymethyl)-cis-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one

Into a 100-mL round-bottom flask was placedrac-cis-3,4-dihydroxy-trans-5-(hydroxymethyl)tetra hydrofuran-2-one (3g, 20.2 mmol, 1 equiv), TsOH.H₂O (385 mg, 2.03 mmol, 0.100 equiv), andanhydrous acetone (60 mL), then 2,2-dimethoxypropane (2.53 g, 24.3 mmol,1.20 equiv) was added at 0° C. over 5 min. The resulting solution wasstirred at 25° C. for 2 h. Then the sodium bicarbonate solid (255 mg,3.04 mmol, 0.150 equiv.) was added to the mixture and stirred for 5 min.The reaction mixture was filtered and concentrated under vacuum. Thisresulted in 3.8 g (100%) of the title compound as a white solid.

Step 2: Synthesis ofrac-((cis)-2,2-dimethyl-6-oxotetrahydrofuro[3,4-d][1,3]dioxol-trans-4-yl)methylmethanesulfonate

Into a 100-mL round-bottom flask was placedrac-trans-6-(hydroxymethyl)-cis-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one(3.81 g, 20.3 mmol, 1 equiv) and TEA (4.10 g, 40.5 mmol, 2 equiv), andTHF (70 mL), then MsCl (2.78 g, 24.3 mmol, 1.20 equiv) was addeddropwise at 0° C. The resulting solution was stirred at 25° C. for 1 h.The mixture was diluted with DCM (20 mL) and washed with the saturatedaqueous NH₄Cl (20 mL×3). The organic layer was dried over MgSO₄,filtered and concentrated under vacuum. This resulted in 5.0 g (93%) ofthe title compound as an orange oil, which was used directly for nextstep without further purification.

Analytical data: LC-MS: (ES, m/z): RT=0.274 min, LCMS: m/z=267 [M+1], ¹HNMR (400 MHz, CDCl₃) δ 4.89-4.73 (m, 3H), 4.54-4.41 (m, 2H), 3.06 (s,3H), 1.49 (s, 3H), 1.41 (s, 3H).

Step 3: Synthesis ofrac-(trans)-6-(azidomethyl)-cis-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one

Into a 100-mL round-bottom flask was placedrac-((cis)-2,2-dimethyl-6-oxotetrahydrofuro[3,4-d][1,3]dioxol-trans-4-yl)methylmethanesulfonate (5.00 g, 18.8 mmol, 1 equiv), NaN₃ (3.66 g, 56.3 mmol,3 equiv), and DMF (60 mL). The resulting solution was stirred at 75° C.for 3 h in an oil bath. The reaction mixture was diluted with EA (150mL) and washed with brine (50 mL×3). The collected organic phase wasdried over Na₂SO₄, filtered and concentrated under vacuum. This resultedin 3.2 g (80%) of the title compound as red oil.

Analytical Data: ¹H NMR (400 MHz, CDCl₃) δ 4.85 (d, J=5.6 Hz, 1H),4.71-4.58 (m, 2H), 3.83-3.74 (m, 1H), 3.70-3.62 (m, 1H), 1.48 (s, 3H),1.39 (s, 3H).

Step 4: Synthesis of rac-(allcis)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridin-4(3aH)-one

Into a 100-mL round-bottom flask was placedrac-(trans)-6-(azidomethyl)-cis-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one(3.20 g, 15.0 mmol, 1 equiv), Pd/C (300 mg, 10% purity), and MeOH (30mL) under N₂ atmosphere. The resulting solution was stirred at 25° C.for 3 h under H₂ (50 psi) atmosphere. The mixture was filtered andconcentrated under vacuum. This resulted in 2.7 g (93%) of the titlecompound as colorless oil.

Analytical Data: ¹H NMR (400 MHz, CDCl₃) δ 7.03-6.83 (m, 1H), 4.58-4.47(m, 2H), 4.12-4.04 (m, 1H), 3.49-3.40 (m, 1H), 3.28-3.20 (m, 1H), 1.54(s, 3H), 1.42 (s, 3H).

Step 5: Synthesis of rac-(allcis)-2,2-dimethylhexahydro-[1,3]dioxolo[4,5-c]pyridin-7-ol

Into a 100-mL round-bottom flask was placed rac-(allcis)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridin-4(3aH)-one(2.55 g, 13.6 mmol, 1 equiv), LiAlH₄ (2.58 g, 68.1 mmol, 5.00 equiv) inTHF (50 mL) was stirred at 70° C. for 6 h under N₂ atmosphere. Thereaction mixture was quenched with H₂O (3 mL). The reaction mixture wasdiluted with EA/MeOH (100 mL, v/v=20/1), dried over Na₂SO₄, filtered andconcentrated under vacuum. This resulted in 2.4 g (crude) of the titlecompound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.086 min, LCMS: m/z=174 [M+1].

Step 6: Synthesis of rac-(all cis)-benzyl7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylate

Into a 100-mL round-bottom flask was placed rac-(allcis)-2,2-dimethylhexahydro-[1,3]dioxolo[4,5-c]pyridin-7-ol (2.36 g, 13.6mmol, 1 equiv), NaHCO₃ (3.43 g, 40.9 mmol, 3 equiv), CbzCl (2.56 g, 15.0mmol, 1.10 equiv), and THF (50 mL). The resulting solution was stirredat 50° C. for 2 h in an oil bath. The mixture was filtered andconcentrated under vacuum. The residue was purified by columnchromatography (SiO₂, PE/EA=3/1 and DCM/MeOH=20/1). This resulted in 2.3g (53%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.665 min, LCMS: m/z=308 [M+1], ¹HNMR (400 MHz, CDCl₃) δ 7.41-7.30 (m, 5H), 5.15 (s, 2H), 4.45-4.35 (m,2H), 4.04-3.82 (m, 1H), 3.76-3.62 (m, 2H), 3.58-3.49 (m, 1H), 3.30-3.20(m, 1H), 2.30 (s, 1H), 1.49 (s, 3H), 1.38 (s, 3H).

Step 7: Synthesis of rac-(all cis)-benzyl7-fluoro-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylate

Into a 50-mL round-bottom flask was placed rac-(allcis)-benzyl-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylate(500 mg, 1.63 mmol, 1 equiv) and dry DCM (8 mL), DAST (786 mg, 4.88mmol, 3 equiv) was added at 0˜10° C. The resulting solution was stirredat 0˜10° C. for 1 h. The reaction mixture was quenched with thesaturated aqueous NaHCO₃ till pH ˜8 and extracted with DCM (20 mL×3).The combined organic layer was dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by column chromatography (SiO₂,PE/EA=3/1 and EA/MeOH=20/1). This resulted in 0.38 g (75%) of the titlecompound as colorless oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.741 min, LCMS: m/z=310 [M+1]. ¹HNMR (400 MHz, CDCl₃) δ 7.38-7.32 (m, 5H), 5.16 (s, 2H), 4.92-4.64 (m,1H), 4.48-4.30 (m, 2H), 3.80-3.58 (m, 4H), 1.51 (s, 3H), 1.39 (s, 3H).

Step 8: Synthesis of rac-(all cis)-benzyl3-fluoro-4,5-dihydroxypiperidine-1-carboxylate

Into a 50-mL round-bottom flask was placed rac-(allcis)-benzyl-7-fluoro-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylate(383 mg, 1.24 mmol, 1 equiv), HCl/MeOH (10.1 mL, 32.6 equiv, 4 mol/L).The resulting solution was stirred at 25° C. for 2 h. The mixture wasconcentrated under vacuum. This resulted in 0.28 g (84%) of the titlecompound as white solid.

Analytical Data: ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.31 (m, 5H), 5.16 (s,2H), 4.73-4.52 (m, 1H), 4.02-3.51 (m, 6H).

Step 9: Synthesis of rac-(all cis)-benzyl3-fluoro-5-hydroxy-4-methoxypiperidine-1-carboxylate and(3R,4S,5S)-benzyl 3-fluoro-4-hydroxy-5-methoxypiperidine-1-carboxylate

Into a 25-mL round-bottom flask was placed rac-(all cis)-benzyl3-fluoro-4,5-dihydroxypiperidine-1-carboxylate (110 mg, 409 μmol, 1equiv), Ag₂O (94.7 mg, 409 μmol, 1 equiv.), MeI (145 mg, 1.02 mmol, 2.50equiv.), and DMF (3 mL). The resulting solution was stirred at 25° C.for 24 h. The mixture was filtered, diluted with EA (30 mL) and washedwith the brine (30 mL×3), the collected organic phase was dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby Prep-HPLC; mobile phase; water (10 mmol/L NH₄HCO₃) and ACN (18.0% ACNup to 38.0% in 10 min); detector, UV 254/220 nm. This resulted in 20 mg(17%) of the title compound as a colorless oil.

Analytical Data: LC-MS: (ES, m/z): RT=0.689 min, LCMS: m/z=284 [M+1], ¹HNMR (400 MHz, CDCl₃) δ 7.43-7.30 (m, 5H), 5.20-5.10 (m, 2H), 4.65-4.43(m, 1H), 4.10-4.05 (m, 1H), 3.86-3.82 (m, 1H), 3.76-3.29 (m, 7H), 2.68(s, 1H). And 32 mg (28%) of the title compound B as colorless oil. [27]LC-MS: (ES, m/z): RT=0.705 min, LCMS: m/z=284 [M+1]. ¹H NMR (400 MHz,CDCl₃) δ=7.43-7.29 (m, 5H), 5.20-5.09 (m, 2H), 4.76-4.51 (m, 1H),3.89-3.61 (m, 5H), 3.59 (s, 3H), 3.40-3.30 (m, 1H), 2.50 (s, 1H).

Step 10: Synthesis of rac-(all cis)-5-fluoro-4-methoxypiperidin-3-ol

Into a 25 mL round-bottom flask was placed rac-(all cis)-benzyl3-fluoro-5-hydroxy-4-methoxypiperidine-1-carboxylate and rac-(allcis)-benzyl 3-fluoro-4-hydroxy-5-methoxypiperidine-1-carboxylate (5.00mg, 17.7 μmol, 1 equiv.), Pd/C (5 mg, 10% purity), and THF (1 mL). Theresulting solution was stirred under H2 (15 psi) at 25° C. for 2 h. Themixture was filtered and concentrated under vacuum. This resulted in 2.6mg (100%) of the title compound as a yellow solid.

Step 11: Synthesis of rac-(allcis)-1-(4-aminopyrimidin-2-yl)-5-fluoro-4-methoxypiperidin-3-ol

Into a 250-mL round-bottom flask was placed 2-chloropyrimidin-4-amine(2.28 mg, 17.6 umol, 1 equiv), rac-(allcis)-5-fluoro-4-methoxy-piperidin-3-ol (2.63 mg, 17.6 μmol, 1 equiv),DIEA (4.56 mg, 35.3 μmol, 2 equiv), and DMSO (1 mL). The resultingsolution was stirred at 100° C. for 12 h. The mixture was filtered andconcentrated under vacuum. The residue was purified by silica gelprep-TLC (PE:EA=1:2). This resulted in 3.5 mg (81%) of the titlecompound.

Analytical Data: LC-MS: (ES, m/z): RT=0.077 min, LCMS: m/z=243 [M+1].

Example B75: Synthesis of rac-(allcis)-1-(4-aminopyrimidin-2-yl)-3-fluoro-5-methoxypiperidin-4-ol

Step 1: Synthesis of rac-(all cis)-3-fluoro-5-methoxypiperidin-4-ol

Into a 25-mL round-bottom flask was placed rac-(all cis)-benzyl3-fluoro-4-hydroxy-5-methoxypiperidine-1-carboxylate (50.0 mg, 176 μmol,1 eq), Pd/C (15.0 mg, 10% purity), and THF (3 mL). The resultingsolution was stirred under H2 (15 psi) at 25° C. for 2 h. The reactionwas filtered and concentrated in vacuo to give the title compound. Thisresulted in 28 mg (100%) of the title compound as colorless oil.

Analytical Data: ¹H NMR (400 MHz, CDCl₃) δ 7.03-6.83 (m, 1H), 4.58-4.47(m, 2H), 4.12-4.04 (m, 1H), 3.49-3.40 (m, 1H), 3.28-3.20 (m, 1H), 1.54(s, 3H), 1.42 (s, 3H).

Step 2: Synthesis of rac-(allcis)-1-(4-aminopyrimidin-2-yl)-3-fluoro-5-methoxypiperidin-4-ol

Into a 25-mL round-bottom flask was placed rac-(allcis)-3-fluoro-5-methoxypiperidin-4-ol (28.0 mg, 188 μmol, 1 eq),2-chloropyrimidin-4-amine (36.5 mg, 282 μmol, 1.50 eq), DIEA (60.6 mg,469 μmol, 2.50 eq), CsF (28.5 mg, 188 μmol, 1 eq), and in DMSO (1 mL).The resulting solution was stirred at 100° C. for 36 h. The reactionmixture was filtered and concentrated under vacuum. The residue waspurified by Prep-HPLC; mobile phase: water (10 mmol/L NH₄HCO₃) and ACN(0% ACN up to 20.0% in 10 min); detector, UV 254/220 nm. This resultedin 15 mg (33%) of the title compound as yellow solid.

Analytical Data: ¹H NMR (400 MHz, CDCl₃) 7.93 (d, J=5.6 Hz, 1H), 5.79(d, J=5.6 Hz, 1H), 4.73 (s, 1H), 4.60 (s, 2H), 4.33-4.14 (m, 3H),3.89-3.83 (m, 1H), 3.70-3.60 (m, 1H), 3.49 (s, 3H), 3.40-3.30 (m, 1H).

Example B76: Synthesis of rac-2-((allcis)-3-fluoro-4,5-dimethoxypiperidin-1-yl)pyrimidin-4-amine

Step I: Synthesis of rac-(3S,4R,5R)-3-fluoro-4,5-dimethoxypiperidine

Into a 25-mL round-bottom flask was placed rac-benzyl-(allcis)-3-fluoro-4,5-dimethoxy-piperidine-1-carboxylate (Resulting fromover-alkylation in Step 9, Example B74; 30.0 mg, 101 μmol, 1 equiv.),Pd/C (10.0 mg, 101 μmol, 10% purity), and THF (2 mL). The resultingsolution was stirred at 25° C. for 2 h under H₂ (15 psi) atmosphere. Themixture was filtered and concentrated under vacuum. This resulted in 16mg (100%) of the title compound as colorless oil.

Step 2: Synthesis of rac-2-((allcis)-3-fluoro-4,5-dimethoxypiperidin-1-yl)pyrimidin-4-amine

Into a 25-mL round-bottom flask was placed rac-(allcis)-3-fluoro-4,5-dimethoxy-piperidine (16 mg, 98.1 μmol, 1 equiv.),2-chloropyrimidin-4-amine (25.4 mg, 196 μmol, 2 equiv.), DIEA (38.0 mg,294 μmol, 51.2 μL, 3 equiv.), CsF (29.8 mg, 196 μmol, 2 equiv.), andDMSO (1 mL). The resulting solution was stirred at 120° C. for 72 h. Themixture was diluted with EA (20 mL) and washed with H₂O (5 mL×3). Thecollected water phases were concentrated under vacuum. The residue waspurified by Prep-HPLC; water (10 mmol/L NH₄HCO₃) and ACN (0% ACN up to30.0% in 10 min); detector, UV 254/220 nm. This resulted in 8.0 mg (32%)of the title compound as colorless oil.

Analytical Data: LC-MS: (ES, m/z): RT=1.141 min, LCMS: m/z=257 [M+1].

Example B77: Synthesis ofrac-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxy-piperidin-3-ol

Step 1: Synthesis of rac-benzyl3,3-difluoro-5-hydroxy-4-methoxy-piperidine-1-carboxylate

To a solution of rac-benzyl3,3-difluoro-4,5-dihydroxy-piperidine-1-carboxylate (as prepared fromStep 2 (Boc-protected) Example 54, 170 mg, 591 μmol, 1 equiv.) and Ag₂O(137 mg, 591 μmol, 1 equiv.) in DMF (5 mL) was added MeI (210 mg, 1.48mmol, 92.1 μL, 2.50 equiv.) dropwise, the mixture was stirred at 25° C.for 16 h while being kept away from light. The mixture was diluted withwater (60 mL) and extracted with EA (40 mL×3), the combined organiclayers were washed with brine (50 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuum. The crude was purified withprep-HPLC [column: Xtimate C18 150*40 mm*10 um; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 31%-51%, 10 min]. This resultedin 110 mg (61%) of the title compound as a colorless oil.

Analytical Data: 1H NMR (400 MHz, CDCl₃) δ 7.44-7.30 (m, 5H), 5.17 (s,2H), 4.32-3.99 (m, 2H), 3.91-3.81 (m, 1H), 3.65 (s, 3H), 3.63 (d, J=3.6Hz, 1H), 3.53-3.27 (m, 1H), 3.07-2.88 (m, 1H), 2.37 (s, 1H).

Step 2: Synthesis of rac-5,5-difluoro-4-methoxy-piperidin-3-ol

To a solution of rac-benzyl3,3-difluoro-5-hydroxy-4-methoxy-piperidine-1-carboxylate (100 mg, 331μmol, 1 equiv.) in THF (5 mL) was added Pd/C (10 mg, 10% purity) underN₂. The mixture was stirred under H₂ (15 psi) at 25° C. for 1 h. Themixture was filtered and the filter was concentrated. The reactionmixture was filtered and the filter was concentrated. This resulted in50 mg (90%) of the title compound as a colorless oil which was used fornext step directly.

Step 3: Synthesis ofrac-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxy-piperidin-3-ol

To a solution of rac-5,5-difluoro-4-methoxy-piperidin-3-ol (50.0 mg, 299μmol, 1 equiv) and DIEA (77.3 mg, 598 μmol, 2 equiv) in DMSO (1 mL) wasadded 2-chloropyrimidin-4-amine (50.3 mg, 388 μmol, 1.30 equiv), themixture was stirred at 120° C. for 16 h. The reaction mixture waspurified with prep-HPLC [column: Waters Xbridge 150*25 mm*5 um; mobilephase: [water (10 mM NH₄HCO₃)-ACN]; B %: 5%-38%, 10 min]. This resultedin 25 mg (32%) of the title compound as a colorless oil.

Analytical Data: 1H NMR (400 MHz, CD₃OD) δ 7.72 (d, J=6.0 Hz, 1H), 5.85(d, J=6.0 Hz, 1H), 4.75-4.66 (m, 1H), 4.58 (s, 1H), 4.47 (dd, J=4.8,12.8, Hz, 1H), 3.75 (dd, J=10.4, 4.4 Hz, 1H), 3.60 (s, 4H), 3.36 (d,J=13.6 Hz, 1H), 3.03 (dd, J=12.4, 11.2 Hz, 1H).

Example B78: S Synthesis ofrac-cis-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol

Step 1: Synthesis ofrac-cis-1-(4-methylsulfanylpyrimidin-2-yl)piperidine-3,4-diol

To a solution of rac-cis-piperidine-3,4-diol (0.500 g, 3.26 mmol, 1equiv., HCl salt) and DIEA (1.68 g, 13.0 mmol, 2.27 mL, 4.00 equiv.) inDMSO (5 mL) was added 2-chloro-4-methylsulfanyl-pyrimidine (784 mg, 4.88mmol, 1.50 equiv.), the mixture was stirred at 100° C. for 16 h. Themixture was diluted with water (120 mL) and extracted with EA (70 mL×2),the combined organic layers were washed with brine (50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuum. The crude waspurified with silica gel column chromatograph (PE:EA=2:1). This resultedin 0.68 g (96%) of the title compound as an off-white solid.

Analytical Data: 1H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=5.2 Hz, 1H), 6.42(d, J=5.2 Hz, 1H), 4.24-4.17 (m, 1H), 4.16-4.07 (m, 1H), 3.96-3.86 (m,2H), 3.73 (dd, J=13.6, 3.2 Hz, 1H), 3.64-3.52 (m, 1H), 2.50 (s, 3H),1.94-1.73 (m, 2H).

Step 2: Synthesis ofrac-cis-4-(2-methoxyethoxy)-1-(4-methylsulfanylpyrimidin-2-yl)piperidin-3-ol

To a solution ofrac-cis-1-(4-methylsulfanylpyrimidin-2-yl)piperidine-3,4-diol (470 mg,1.95 mmol, 1 equiv.), NaI (29.2 mg, 194 μmol, 0.100 equiv.) in ACN (10mL) was added 2-methoxyethyl 4-methylbenzenesulfonate (897 mg, 3.90mmol, 2 equiv.) and Cs₂CO₃ (1.90 g, 5.84 mmol, 3 equiv.), the mixturewas stirred at 80° C. for 16 h. The mixture was filtered and thefiltrate was concentrated in vacuo. The crude was purified withprep-HPLC [column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase:[water (0.225% FA)-ACN]; B %: 1%-25%, 9 min]. This resulted in 0.18 g(30%) of the title compound as a yellow solid.

Analytical Data: 1H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=5.2 Hz, 1H), 6.39(d, J=5.2 Hz, 1H), 4.07-4.02 (m, 1H), 3.97-3.79 (m, 4H), 3.71-3.65 (m,1H), 3.61-3.47 (m, 3H), 3.42-3.38 (m, 3H), 2.50 (s, 3H), 2.01-1.89 (m,1H), 1.78-1.66 (m, 1H).

Step 3: Synthesis ofrac-cis-4-(2-methoxyethoxy)-1-(4-methylsulfonylpyrimidin-2-yl)piperidin-3-ol

[8] To a solution ofrac-cis-4-(2-methoxyethoxy)-1-(4-methylsulfanylpyrimidin-2-yl)piperidin-3-ol(160 mg, 534 μmol, 1 equiv.) in THF (8 mL) and H₂O (2 mL) was addedOxone (1.64 g, 2.67 mmol, 5.00 equiv.), the mixture was stirred at 25°C. for 1 h. The mixture was washed with saturated aqueous Na₂SO₃ (20 mL)and extracted with EA (30 mL×3), the combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuum. The crudewas purified with silica gel chromatograph (EA). This resulted in 85 mg(48%) of the title compound as a colorless oil.

Analytical Data: 1H NMR (400 MHz, CDCl₃) δ 8.58 (d, J=4.8 Hz, 1H), 7.07(d, J=4.8 Hz, 1H), 4.08-3.94 (m, 3H), 3.93-3.85 (m, 2H), 3.84-3.80 (m,1H), 3.75-3.63 (m, 2H), 3.60-3.49 (m, 3H), 3.42-3.38 (m, 3H), 3.18 (s,3H), 2.01-1.90 (m, 1H), 1.79-1.69 (m, 1H).

Step 4: Synthesis ofrac-cis-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol

A solution ofrac-cis-4-(2-methoxyethoxy)-1-(4-methylsulfonylpyrimidin-2-yl)piperidin-3-ol(80.0 mg, 241 μmol, 1 equiv) in NH₃/THF (8 mL) was stirred at 25° C. for16 h. The mixture concentrated in vacuo. The crude was purified withprep-HPLC [column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water(10 mM NH₄HCO₃)-ACN]; B %: 1%-30%, 10 min]. This resulted in 5.0 mg (7%)of the title compound as a mixture of enantiomers as a colorless oil.

Analytical Data: 1H NMR (400 MHz, CDCl₃) δ 7.91 (d, J=5.6 Hz, 1H), 5.73(d, J=5.6 Hz, 1H), 4.57 (s, 2H), 4.00-3.93 (m, 1H), 3.91-3.82 (m, 2H),3.82-3.72 (m, 3H), 3.71-3.60 (m, 3H), 3.59-3.56 (m, 1H), 3.40 (s, 3H),2-1.90 (m, 1H), 1.73-1.67 (m, 1H).

Example B79: Synthesis of trans racemic(3S,4S)-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol

Step 1: Synthesis ofrac-trans-tert-butyl-3,4-dihydroxypiperidine-1-carboxylate

A solution of racemic tert-butyl7-oxa-4-azabicyclo[4.1.0]heptane-4-carboxylate (2 g, 10.0 mmol, 1equiv.) in dioxane (30 mL) was added a solution of KOH (1.13 g, 20.0mmol, 2 equiv.) in water (15 mL), the mixture was stirred at 100° C. for16 h. The mixture was concentrated in vacuo to give a residue. Theresidue was diluted with water (200 mL), extracted with EA (100 mL×3).The combined organic layers were washed with brine (80 mL), dried andconcentrated in vacuo. This resulted in 2 g (90%) of the title compoundas a colorless oil which was used for next step directly.

Step 2: Synthesis of (3S,4S)-piperidine-3,4-diol

A solution of rac-trans-tert-butyl-3,4-dihydroxypiperidine-1-carboxylate(2 g, 9.21 mmol, 1 equiv.) in HCl/dioxane (5 mL, 4 mol/L) was stirred at25° C. for 30 min. The mixture was concentrated in vacuo. This resultedin 1.40 g (100%) of the title compound as a yellow solid which was usedfor next step directly.

Step 3: Synthesis ofrac-trans-1-(4-methylsulfanylpyrimidin-2-yl)piperidine-3,4-diol

To a solution of rac-trans-piperidine-3,4-diol (1.20 g, 7.81 mmol, 1equiv., HCl salt) and DIEA (5.05 g, 39.1 mmol, 6.80 mL, 5.00 equiv.) inDMSO (12 mL) was added 2-chloro-4-methylsulfanyl-pyrimidine (1.25 g,7.81 mmol, 1 equiv.), the mixture was stirred at 100° C. for 16 h. Themixture was diluted with water (150 mL) and extracted with EA (100mL×2), the combined organic layers were washed with brine (80 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuum. The crudewas purified with silica gel column chromatograph (PE:EA=2:1). Thisresulted in 1.30 g (69%) of the title compound as an off-white solidwhich was used for next step directly.

Step 4: Synthesis ofrac-trans-4-(2-methoxyethoxy)-1-(4-methylsulfanylpyrimidin-2-yl)piperidin-3-ol

To a solution ofrac-trans-1-(4-methylsulfanylpyrimidin-2-yl)piperidine-3,4-diol (700 mg,2.90 mmol, 1 equiv), NaI (43.4 mg, 290 μmol, 0.100 equiv.) in ACN (10mL) was added 2-methoxyethyl 4-methylbenzenesulfonate (1.34 g, 5.80mmol, 2 equiv.) and Cs₂CO₃ (2.84 g, 8.70 mmol, 3 equiv.), the mixturewas stirred at 80° C. for 16 h. The mixture was filtered and thefiltrate was concentrated in vacuo. The crude was purified withprep-HPLC [column: Waters Xbridge C18 150*50 mm*10 um; mobile phase:[water (10 mM NH4HCO3)-ACN]; B %: 20%-50%, 11.5 min]. This resulted in300 mg (34%) of the title compound as a yellow solid.

Analytical Data: 1H NMR (400 MHz, CDCl₃) δ 8.00-7.93 (m, 1H), 6.46-6.39(m, 1H), 5.03-4.83 (m, 1H), 4.81-4.62 (m, 1H), 4.02-3.88 (m, 1H),3.74-3.57 (m, 5H), 3.42 (s, 3H), 3.38-3.14 (m, 1H), 3.03-2.65 (m, 2H),2.50 (s, 3H), 2.08-2.01 (m, 1H), 1.56-1.46 (m, 1H).

Step 5: Synthesis ofrac-trans-4-(2-methoxyethoxy)-1-(4-methylsulfonylpyrimidin-2-yl)piperidin-3-ol

To a solution ofrac-trans-4-(2-methoxyethoxy)-1-(4-methylsulfanylpyrimidin-2-yl)piperidin-3-ol(300 mg, 1 mmol, 1 equiv.) in THF (10 mL) and H₂O (3 mL) was added Oxone(1.85 g, 3.01 mmol, 3 equiv.), the mixture was stirred at 25° C. for 3h. The mixture was washed with saturated aqueous Na₂SO₃ (60 mL) andextracted with EA (50 mL×3), the combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuum. The crude waspurified with silica gel chromatograph (EA). This resulted in 120 mg(36%) of the title compound as a colorless oil.

Step 6: Synthesis ofrac-trans-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol

A solution ofrac-trans-4-(2-methoxyethoxy)-1-(4-methylsulfonylpyrimidin-2-yl)piperidin-3-ol(120 mg, 362 μmol, 1 equiv) in NH₃/THF (8 mL) was stirred at 25° C. for16 h. The mixture was concentrated in vacuo. The crude was purified withprep-HPLC [column: Xtimate C18 150*40 mm*10 um; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 10%-20%, 10 min]. This resultedin 10.0 mg (10%) of the title compound as a mixture of enantiomers as acolorless oil.

Analytical Data: 1H NMR (400 MHz, CDCl₃) δ 7.90 (d, J=5.6 Hz, 1H), 5.74(d, J=5.6 Hz, 1H), 4.74-4.64 (m, 3H), 4.57-4.49 (m, 1H), 3.90-3.84 (m,1H), 3.70-3.65 (m, 1H), 3.60-3.55 (m, 3H), 3.40 (s, 3H), 3.39-3.29 (m,1H), 3.01-2.94 (m, 1H), 2.88 (dd, J=13.2, 9.6 Hz, 1H), 2.03-2 (m, 1H),1.53-1.43 (m, 1H).

Example C1: Synthesis of 1,6-dichloro-4-isopropyl-2,7-naphthyridine

Step 1: Synthesis of 6-chloro-4-iodo-2,7-naphthyridin-1(2H)-one

To a solution of 6-chloro-1,2-dihydro-2,7-naphthyridin-1-one (50 g,0.276 mol) in DMF (300 mL), NIS (74 g, 0.33 mol) was added at 0° C. andthe mixture was stirred overnight at rt. The reaction mixture wasfiltered and the filtered cake was washed by water and dried undervacuum to afford the title compound (60 g, 70%) as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=307 [M+1]. 1H NMR (300 MHz, DMSO-d6) δ12 (s, 1H), 9.02 (s, 1H), 7.89 (d, 1H, J=6.0 Hz), 7.44 (s, 1H).

Step 2: Synthesis of 1,6-dichloro-4-iodo-2,7-naphthyridine

A mixture of 6-chloro-4-iodo-1,2-dihydro-2,7-naphthyridin-1-one (60 g,0.196 mol) in POCl₃ (320 mL) was stirred at 100° C. for 1.5 h. LCMSshowed the starting material was consumed. The mixture was concentratedand neutralized with cooled saturated aq. NaHCO₃. The mixture wasextracted with EA 3*300 mL. The combined organic layers were dried overNa₂SO₄, filtered and concentrated in reduced pressure to give1,6-dichloro-4-iodo-2,7-naphthyridine 53 g (84%) as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=325 [M+1].

Step 3: Synthesis of 1,6-dichloro-4-(prop-1-en-2-yl)-2,7-naphthyridine

To a solution of 1,6-dichloro-4-iodo-2,7-naphthyridine (30 g, 92.5 mmol)in 1,4-dioxane/H₂O (300/70 mL) was added4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (15 g, 93mmol), K₂CO₃ (37.8 g, 276 mmol) andPdAMPhosCl₂/Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(3 g, 4.2 mmol). The resulting solution was stirred for 0.5 h at 50° C.LCMS showed the reaction is complete. The mixture was cooled to rt anddiluted with 200 mL of water. The resulting solution was extracted with2×300 mL of EA and the organic layers combined. The resulting mixturewas washed with 200 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The product was purifiedby chromatography with EA:PE (1:10). This resulted in 15 g (68.1%) of1,6-dichloro-4-(prop-1-en-2-yl)-2,7-naphthyridine as white solid.

Analytical Data: LC-MS: (ES, m/z)=239 [M+1].

Step 4: Synthesis of 1,6-dichloro-4-isopropyl-2,7-naphthyridine

To a solution of 1,6-dichloro-4-(prop-1-en-2-yl)-2,7-naphthyridine (4 g,16.8 mmol) in EA (300 mL) was added PtO₂ (5 g, 22 mmol). The resultingmixture was stirred at 25° C. for 24 h under H₂ atmosphere. The solidwas filtered out. The filtrate was concentered under vacuum. The residuewas purified by chromatography (EA:PE=1:8) to give 3 g (75%) of1,6-dichloro-4-(propan-2-yl)-2,7-naphthyridine as a white solid.

Analytical Data: LC-MS: (ES, m/z)=241 [M+1]. 1H NMR (300 MHz, DMSO-d6) δ9.47 (d, 1H, J=0.8 Hz), 8.47 (d, 1H, J=0.7 Hz), 8.26 (d, 1H, J=0.8 Hz),3.64 (p, 1H, J=6.8 Hz), 1.33 (d, 6H, J=6.9 Hz).

Example C2: Synthesis of 4-bromo-7-chloro-1-isopropyl-2,6-naphthyridine

Step 1: Synthesis of 5-bromo-N-tert-butyl-2-chloroisonicotinamide

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed 5-bromo-2-chloropyridine-4-carboxylicacid (4 g, 16.9 mmol) in DMF (30 mL), 2-methylpropan-2-amine (1.47 g,20.2 mmol), EDC HCl (4.85 g, 25.3 mmol) and HOBT (3.41 g, 25.3 mmol).The resulting solution was stirred overnight at rt. The resultingsolution was added water and suspension was extracted with EA, and thenthe organic layers were combined, dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified by FLASH withPE/EA (2:1). This resulted in 3 g (60.9%) of5-bromo-N-tert-butyl-2-chloropyridine-4-carboxamide as a white solid.

Analytical Data: LC-MS: (ES, m/z)=293 [M+1]; 1H NMR (300 MHz, DMSO-d6) δ8.64 (s, 1H), 8.30 (s, 1H), 7.58 (s, 1H), 1.36 (s, 9H).

Step 2: Synthesis of(E)-N-tert-butyl-2-chloro-5-(2-ethoxyvinyl)isonicotinamide

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed5-bromo-N-tert-butyl-2-chloropyridine-4-carboxamide (2 g, 6.85 mmol) indioxane (30 mL) and H₂O (6 mL),2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.49 g,7.53 mmol), Cs₂CO₃ (4.46 g, 13.7 mmol) and Pd(dppf)Cl₂ (501 mg, 685μmop. The resulting solution was stirred for 2 h at 80° C. The resultingsolution was diluted with water and extracted with EA, and then theorganic layers combined, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by FLASH with PE/EA(2:1). This resulted in 1.2 g (62.1%) ofN-tert-butyl-2-chloro-5-[(E)-2-ethoxyethenyl]pyridine-4-carboxamide as ayellow solid.

Analytical Data: LC-MS: (ES, m/z)=283 [M+1]; 1H NMR (300 MHz, DMSO-d6) δ8.55 (s, 1H), 8.20 (s, 1H), 7.35 (d, 1H, J=13.0 Hz), 7.28 (s, 1H), 5.79(d, 1H, J=13.0 Hz), 3.90 (q, 2H, J=7.0 Hz), 1.35 (s, 9H), 1.26 (t, 3H,J=7.0 Hz).

Step 3: Synthesis of 7-chloro-2,6-naphthyridin-1(2H)-one

Into a 20-mL vial was placedN-tert-butyl-2-chloro-5-[(E)-2-ethoxyethenyl]pyridine-4-carboxamide (1.2g, 4.24 mmol) in TFA (20 mL). The resulting solution was stirredovernight at 100° C. The resulting mixture was concentrated undervacuum. This resulted in 600 mg (91.5%) of7-chloro-1,2-dihydro-2,6-naphthyridin-1-one as a red solid. The crudeproduct was used directly for next step without any furtherpurification.

Analytical Data: LC-MS: (ES, m/z)=181 [M+1].

Step 4: Synthesis of 4-bromo-7-chloro-2,6-naphthyridin-1(2H)-one

Into a 250-mL round-bottom flask was placed7-chloro-1,2-dihydro-2,6-naphthyridin-1-one (3 g, 16.6 mmol) in DCM (40mL) and NBS (3.54 g, 19.9 mmol). The resulting solution was stirred for1 h at rt. The solid was collected by filtration. This resulted in 3 g(69.7%) of the title compound as a white solid.

Analytical Data: LC-MS: (ES, m/z)=261 [M+1]; H NMR (300 MHz, DMSO-d₆) δ12.09 (s, 1H), 8.93 (s, 1H), 8.04 (s, 1H), 7.70 (d, 1H, J=6.0 Hz).

Step 5: Synthesis of 4-bromo-7-chloro-2,6-naphthyridin-1-yltrifluoromethanesulfonate

Into a 50-mL three-necked bottle was placed4-bromo-7-chloro-1,2-dihydro-2,6-naphthyridin-1-one (1 g, 3.85 mmol) inDCM (15 mL) and TEA (777 mg, 7.70 mmol). The resulting mixture wascooled to −78° C., and then Tf₂O (4.34 g, 15.4 mmol) was added drop wiseover 10 min. The resulting solution was stirred for 0.5 h at −78° C.Then the mixture was warmed to room temperature and stirred at thistemperature for 0.5 h. The reaction was then quenched by the addition of2 mL of water/ice, extracted with DCM, and then the organic layerscombined, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column with EA/PE(0-10%). This resulted in 1 g (66.6%) of the title compound as a whitesolid.

Analytical Data: LC-MS: (ES, m/z)=393 [M+1]; 1H NMR (300 MHz, DMSO-d6) δ9.47 (s, 1H), 8.78 (s, 1H), 8.14 (d, 1H, J=0.9 Hz).

Step 6: Synthesis of 4-bromo-7-chloro-1-iodo-2,6-naphthyridine

Into a 50-mL three-necked bottle was placed4-bromo-7-chloro-2,6-naphthyridin-1-yl trifluoromethanesulfonate (500mg, 1.27 mmol) in ACN (9 mL) and NaI (952 mg, 6.35 mmol). The resultingmixture was cooled to 0° C. and trifluoromethanesulfonate acid (381 mg,2.54 mmol) in ACN (1 mL) was added drop wise over 10 min. The mixturewas then stirred at rt for 1.5 h. After that, the resulting solution wasextracted with EA, and then the organic layers combined, washed withbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. This resulted in 500 mg of the title compound as a dark solid.The crude compound was used directly for next without furtherpurification.

Analytical Data: LC-MS: (ES, m/z)=369 [M+1].

Step 7: Synthesis of4-bromo-7-chloro-1-(prop-1-en-2-yl)-2,6-naphthyridine

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed4-bromo-7-chloro-1-iodo-2,6-naphthyridine (500 mg, 1.35 mmol) was addedin dioxane (5 mL) and H₂O (1 mL),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (226 mg, 1.35mmol), K₂CO₃ (372 mg, 2.7 mmol) and Pd(dppf)Cl₂ (0.99 mg, 0.135 mmol).The resulting solution was stirred for 2 h at 80° C. The resultingsolution was extracted with EA, and then the organic layers combined,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified by Prep-TLC with PE/EA (8:1). This resulted in 200mg (52.3%) of the title compound as a light-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=285 [M+1].

Step 8: Synthesis of 4-bromo-7-chloro-1-isopropyl-2,6-naphthyridine

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of hydrogen, was placed4-bromo-7-chloro-1-(prop-1-en-2-yl)-2,6-naphthyridine (160 mg, 564 μmol)in EA (6 mL) and PtO₂ (166 mg, 733 μmol). The resulting solution wasstirred for 3 h at rt. The solids were filtered out. The resultingmixture was concentrated under vacuum. This resulted in 100 mg (62.1%)of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=287 [M+1].

Example C3: Synthesis of 4,7-dichloro-1-isopropylpyrido[4,3-d]pyridazine

Step 1: Synthesis of 6-chloro-4-isobutyrylnicotinic Acid

To a stirred solution of n-BuLi (100 mL) in THF was added dropwise TMP(40.1 g, 285 mmol) at −78° C. The mixture was allowed to warm to 0° C.and stirred for 1 h and then recooled to −78° C. And then a solution of6-chloropyridine-3-carboxylic acid (15 g, 95.2 mmol) in THF was addeddropwise and the reaction was left to stir for 1.5 h. ThenN-methoxy-N,2-dimethylpropanamide (37.3 g 285 mmol) was added and thereaction mixture was allowed to warm to rt and stirred for 4 h. Themixture was quenched by aq. NH₄Cl and PH was adjusted to 5-6 with citricacid, and then extracted with EA. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure to get the target product as yellow oil without furtherpurification.

Analytical Data: LC-MS: (ES, m/z)=228 [M+1].

Step 2: Synthesis of7-chloro-1-isopropylpyrido[3,4-d]pyridazin-4(3H)-one

To a solution of 6-chloro-4-(2-methylpropanoyl)pyridine-3-carboxylicacid (11 g, 48.3 mmol) in IPA was added NH₂NH₂.H₂O (3.62 g, 72.4 mmol),the mixture was stirred at 70° C. for 3 h. The mixture was filtered andthe solid was collected, the filtrate was concentrated to 10 mL, andthen filtered. The solid was combined to get target product as yellowsolid (6 g, crude).

Analytical Data: LC-MS: (ES, m/z)=224 [M+1].

Step 3: Synthesis of 4,7-dichloro-1-isopropylpyrido[4,3-d]pyridazine

To a solution of POCl₃ (5 mL) was added7-chloro-1-(propan-2-yl)-3H,4H-pyrido[3,4-d]pyridazin-4-one (100 mg, 447umol). The mixture was stirred overnight at 100° C. The mixture wasconcentrated and the product was used directly without furtherpurification.

Analytical Data: LC-MS: (ES, m/z)=242 [M+1].

Example C4: Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline

Step 1: Synthesis of 8-bromo-3-chloroisoquinolin-5-yltrifluoromethanesulfonate

Trifluoromethanesulfonyl trifluoromethanesulfonate (45.7 g, 162 mmol)was added dropwise to 8-bromo-3-chloroisoquinolin-5-ol (14 g, 54.1 mmol)and TEA (21.8 g, 216 mmol) in DCM (400 mL) at −60° C. The resultingmixture was warmed to room temperature naturally and stirred at rt for 1h. The mixture was concentrated under vacuum. The residue was purifiedby a silica gel column with PE:EA=5:1 to afford 18 g (85%) the titlecompound as a white solid.

Analytical Data: LC-MS: (ES, m/z)=392 [M+1]; 1H NMR (400 MHz, DMSO-d6) δ9.46 (d, 1H, J=0.8 Hz), 8.20 (d, 1H, J=8.3 Hz), 8.02 (d, 1H, J=8.4 Hz),7.93 (d, 1H, J=0.7 Hz).

Step 2: Synthesis of 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline

The mixture of K₂CO₃ (6 g, 43.5 mmol), 8-bromo-3-chloroisoquinolin-5-yltrifluoromethanesulfonate (17 g, 43.5 mmol),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (7.30 g, 43.5mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (2.83 g, 3.48 mmol) in dioxane/H₂O (200/20mL) was stirred for 3 h at 45° C. The mixture was diluted with 500 mL ofEA and washed with brine 200 mL*2. The organic layer was dried withNa₂SO₄ and concentrated under vacuum. The residue was purified by asilica gel column with PE:EA=20:1 to afford 8.0 g (67%) the titlecompound as an off-white solid.

Analytical Data: LC-MS: (ES, m/z)=282 [M+1].

Step 3: Synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline

PtO₂ (1.7 g 7.04 mmol) and8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline (7.1 g, 25.1 mmol) in EA(300 mL) were stirred under an atmosphere of H₂ balloon at rt andstirred for 1 h. The solid was filtered out. The mother solvent wasconcentrated under vacuum. The crude product was purified by a silicagel column with PE:EA=10:1 to get 6.7 g (93%) the title compound as abrown solid.

Analytical Data: LC-MS: (ES, m/z)=284 [M+1].

Example C5: Synthesis ofrac-2-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol

Step 1: Synthesis of 2-(8-bromo-3-chloroisoquinolin-5-yl)prop-2-en-1-ol

To a solution of 8-bromo-3-chloroisoquinolin-5-yltrifluoromethanesulfonate (5 g, 12.8 mmol, form step 1 of Example C4) in1,4-dioxane/H₂O was added2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol (2.35 g,12.8 mmol), K₂CO₃ (1.76 g, 12.8 mmol) and Pd(dPPf)Cl₂ (467 mg, 0.641mmol). The resulting solution was stirred for 2 h at 60° C. Theresulting solution was diluted with 100 mL of water and extracted with2×100 mL of EA. The organic phase was washed with brine, dried, andconcentrated. The residue was purified by Flash with PE:EA (1:1). Thisresulted in 2.1 g (54.9%) of the title compound as white solid.

Analytical Data: LC-MS: (ES, m/z)=298 [M+1].

Step 2: Synthesis of rac-2-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol

The mixture of 2-(8-bromo-3-chloroisoquinolin-5-yl)prop-2-en-1-ol (2 g,6.69 mmol) and PtO₂ (454 mg, 0.05 mmol) in EA (50 mL) was stirred at rtfor 2 h at H₂ atmosphere. The resulting mixture was filtered. Thefiltrate was concentered under vacuum. The product was purified by Flashwith PE:EA (10:1). This resulted in 1.8 g (90%) of the title compound asa yellow solid.

Analytical Data: LC-MS: (ES, m/z)=300 [M+1].

Example C6: Synthesis of 8-bromo-3-chloro-5-methylisoquinoline

The mixture of 8-bromo-3-chloroisoquinolin-5-yltrifluoromethanesulfonate (500 mg, 1.28 mmol, from step 1 of ExampleC1), trimethyl-1,3,5,2,4,6-trioxatriborinane (64.2 mg, 512 μmol),Pd(dppf)Cl₂ (46.9 mg, 64.0 μmol) and K₂CO₃ (176 mg, 1.28 mmol) inmixture solvent (dioxane: H₂O=5:1, 4.8 mL) was stirred at 40° C. for 16h under N₂ atmosphere. The resulting solution was concentrated undervacuum. The residue was purified by Prep-TLC with DCM/MeOH (20/1) toafford 100 mg of the title compound as an off-white solid.

Analytical Data: LC-MS: (ES, m/z)=258 [M+1].

Example C7: Synthesis of 8-bromo-3-chloroisoquinoline

The mixture of 8-bromo-3-chloroisoquinolin-5-yltrifluoromethanesulfonate (100.00 mg, 0.256 mmol, 1 equiv., from step 1of Example C4), [3-(diphenylphosphanyl)propyl]diphenylphosphane (2.11mg, 0.005 mmol, 0.02 equiv.), (acetyloxy)palladio acetate (1.15 mg,0.005 mmol, 0.02 equiv.), and triethylsilane (74.43 mg, 0.640 mmol, 2.5equiv) in DMF (3 mL) was stirred for 1 h at 60° C. under N₂ atmosphere.Water was added and extracted with EA and concentrated. The residue wasapplied onto a Prep-TLC with DCM/MeOH (10:1). This resulted in 50 mg(80.5%) of the title compound as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=242 [M+1].

Example C8: Synthesis ofrac-3-chloro-5-(1-fluoropropan-2-yl)-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

Step 1: Synthesis ofrac-2-{3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]isoquinolin-5-yl}propan-1-ol

To a solution of rac-2-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol(150 mg, 0.4990 mmol, from Example C5) in 1,4-dioxane was added3-(methanesulfonylmethyl)azetidine (74.4 mg, 0.499 mmol), Cs₂CO₃ (325mg, 0.998 mmol) and XantPhos Pd G4 (44.3 mg, 49.9 umol) under nitrogen.The mixture was stirred at 100° C. for 3 h. The resulting solution wasdiluted with 20 mL of water and extracted with 2×20 mL of EA. Theorganic phase was washed with brine, dried and concentrated undervacuum. The crude product was purified by Prep-TLC (DCM: MeOH=10:1).This resulted in 100 mg (54.3%) of the title compound as yellow solid.

Analytical Data: LC-MS: (ES, m/z)=369 [M+1].

Step 2: Synthesis ofrac-bn3-chloro-5-(1-fluoropropan-2-yl)-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

To a solution of2-{3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]isoquinolin-5-yl}propan-1-ol(100 mg, 0.2710 mmol) in DCM was added DAST (87.3 mg, 0.542 mmol) at 0°C. The mixture was stirred at 0° C. for 3 h. The reaction solution wasquenched with water and extracted with 2×20 mL of EA. The organic phasewas washed with brine, dried and concentrated under vacuum. The crudeproduct was purified by Prep-TLC (DCM:MeOH=15:1). This resulted in 80 mg(79.9%) of 3 the title compound as yellow solid.

Analytical Data: LC-MS: (ES, m/z)=371 [M+1].

Example C9: Synthesis of 8-bromo-3-chloro-5-ethoxyisoquinoline

Step 1: Synthesis of 8-bromo-3-chloro-5-methoxyisoquinoline

To a mixture of 3-chloro-5-methoxyisoquinoline (2 g, 10.3 mmol) in AcOH(20 mL) was added a solution of dibromine (1.80 g, 11.3 mmol) dissolvedin 10 mL AcOH over 10 min. The mixture was stirred overnight at rt. Themixture was concentrated and the residue was slowly poured into asolution of K₂CO₃ (5 g in 100 mL H₂O) with rapid stirring. Then themixture was extracted with DCM and concentrated in reduced pressure toget the title compound 2.5 g (89.2%) as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=272 [M+1]. 1H-NMR (300 MHz, 6d-DMSO) δppm 9.21 (s, 1H), 8.09-7.81 (m, 2H), 7.20 (d, J=8.3 Hz, 1H), 4.00 (s,3H).

Step 2: Synthesis of 8-bromo-3-chloroisoquinolin-5-ol

To a solution of 8-bromo-3-chloro-5-methoxyisoquinoline (2 g, 7.33 mmol)in DCM was added tribromoborane (5.48 g, 21.9 mmol). The resultingsolution was stirred for 2 h at rt. The reaction mixture was slowlypoured into ice/water with rapid stirring. The precipitation collectedby filtration. This is resulted in 1.8 g (89%) of the title compound asa yellow solid.

Analytical Data: LC-MS: (ES, m/z)=258 [M+1].

Step 3: Synthesis of 8-bromo-3-chloro-5-ethoxyisoquinoline

To a solution of 8-bromo-3-chloroisoquinolin-5-ol (900 mg, 3.48 mmol) inDMF (20 mL) was added iodoethane (1.08 g, 6.96 mmol) and Cs₂CO₃ (3.39 g,10.4 mmol). The resulting solution was stirred for 3 h at 100° C. Theresulting solution was cooled to rt and diluted with water and extractedwith EA. The organic phase was concentrated under vacuum and purified bychromatography with PE:EA (1:1). This resulted in 800 mg (80.2%) of thetitle compound as yellow solid.

Analytical Data: LC-MS: (ES, m/z)=286 [M+1]; 1H-NMR (400 MHz, 6d-DMSO) δppm 9.23 (d, 1H, J=0.8 Hz), 8.03 (d, 1H, J=0.8 Hz), 7.91 (d, 1H, J=8.3Hz), 7.20 (d, 1H, J=8.4 Hz), 4.25 (q, 2H, J=7.0 Hz), 1.47 (t, 3H, J=6.9Hz).

Example C10: Synthesis of3-chloro-8-(3-(cyclopropylsulfonylmethyl)azetidin-1-yl)-5-isopropylisoquinoline

Step 1: Synthesis of(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)methanol

A mixture of 8-bromo-3-chloro-5-(propan-2-yl)isoquinoline (Example C4,300 mg, 1.05 mmol, Example C4), (azetidin-3-yl)methanol hydrochloride(129 mg, 1.05 mmol), XantPhos Pd G4 (175 mg, 210 μmop, Cs₂CO₃ (684 mg,2.10 mmol) in dioxane (25 mL) stirred at 100° C. for 16 h. The reactionwas purified by preparative TLC (DCM:MeOH=15:1) to afford the titlecompound (230 mg, 76%) as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=291 [M+1].

Step 2: Synthesis of3-chloro-8-(3-(iodomethyl)azetidin-1-yl)-5-isopropylisoquinoline

A mixture of{1-[3-chloro-5-(propan-2-yl)isoquinolin-8-yl]azetidin-3-yl}methanol (220mg, 756 μmop, triphenylphosphine (296 mg, 1.13 mmol), imidazole (102 mg,1.51 mmol) and iodine (230 mg, 907 μmol) in DCM (25 mL) was stirred atrt for 2 h. The solvent was removed and the reside was purified bypreparative TLC (PE:EA=20:1) to afford the title compound (190 mg, 62%)as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=401 [M+1].

Step 3: Synthesis of3-chloro-8-(3-(cyclopropylsulfonylmethyl)azetidin-1-yl)-5-isopropylisoquinoline

A mixture of3-chloro-8-[3-(iodomethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline(100 mg, 249 μmop, sodium cyclopropanesulfinate (127 mg, 996 μmol) inDMF (15 mL) was stirred at 80° C. for 2 h. The solvent removed andresidue was purified by preparative TLC (PE:EA=2:1) to afford the titlecompound (100 mg, 94.5%) as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=379 [M+1].

Example C11: Synthesis of 8-bromo-3-chloro-5-cyclopropylisoquinoline

To a solution of 8-bromo-3-chloroisoquinolin-5-yltrifluoromethanesulfonate (240 mg, 614 μmol) in dioxane/H₂O (10 mL/2 mL)was added 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (123 mg,736 μmol) and K₂CO₃ (168 mg, 1.22 mmol) and Pd(dppf)Cl₂ (50.1 mg, 61.4μmol). The mixture was stirred at 80° C. for 16 h under N₂ atmosphere.The mixture was added water and extracted with EA. The organic phase wasconcentrated and purified by FLASH (50% EA in PE) to give the titlecompound of 90 mg (52%) as yellow solid.

Analytical Data: LC-MS: (ES, m/z)=284 [M+1].

Example C12: Synthesis of3-chloro-5-isopropyl-7-methyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

Step 1: Synthesis of7-bromo-3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

To a solution of3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline(150 mg, 425 μmol) in DMF (10 mL) were added NBS (60.1 mg, 340 μmol).The solution was stirred at rt for 16 h. The solvent was removed and theresidue was purified by Prep-TLC (5% MeOH in DCM) to give the titlecompound of 170 mg (81.7%) as yellow solid.

Analytical Data: LC-MS: (ES, m/z)=431 [M+1].

Step 2: Synthesis of3-chloro-5-isopropyl-7-methyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

The mixture of7-bromo-3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline(75 mg, 173 μmol), trimethyl-1,3,5,2,4,6-trioxatriborinane (8.68 mg,69.2 μmol), K₂CO₃ (23.8 mg, 173 μmol) and Pd(dppf)Cl₂ (14.1 mg, 17.3μmol) in dioxane/H₂O (7 mL/2 mL) was stirred for 3 h at 80° C. Themixture was extracted with EA. The organic concentrated and was purifiedby FLASH (5% MeOH in DCM) to give 55 mg (87%) of the title compound ofas yellow solid.

Analytical Data: LC-MS: (ES, m/z)=367 [M+1].

Example C13: Synthesis of3-chloro-7-fluoro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

Step 1: Synthesis of7-bromo-3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

NBS (163 mg, 918 μmol) was added batchwise to3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline(360 mg, 1.02 mmol) in DMF (20 mL) at rt. The resulting mixture wasstirred at rt for 16 h. The mixture was diluted with EA and washed withbrine. The organic layer was dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by a Pre-TLC with PE:EA=1:1 to afford350 mg the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=431 [M+1].

Step 2: Synthesis of3-chloro-7-fluoro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

n-BuLi (2.5 M, 2.29 mmol, 916 μL) was dropwise to7-bromo-3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline(330 mg, 764 μmol) and N-(benzenesulfonyl)-N-fluorobenzenesulfonamide(479 mg, 1.52 mmol) in THF (20 mL) at −78° C. under N₂ atmosphere. Theresulting mixture was stirred at rt for 1 h. The mixture was quenchedwith H₂O, diluted with EA and washed with brine. The organic layer wasdried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by a Pre-TLC with DCM:MeOH=30:1 to afford 80 mg the titlecompound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=371 [M+1].

Example C14: Synthesis of3-chloro-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-5-(trifluoromethyl)isoquinoline

Step 1: Synthesis of3-chloro-5-iodo-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

To a solution of3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]isoquinoline(100 mg, 307 umol) in AcOH (5 mL) was added iodo(sulfanyl)amine (58.6mg, 337 umol) and stirred at rt for 1 h. Water was added and thereaction was extracted with EA. The organic phase was concentrated andpurified by preparative TLC (DCM:MeOH=15:1) to give product (100 mg) asyellow solid.

Analytical Data: LC-MS: (ES, m/z)=451 [M+1].

Step 2: Synthesis of3-chloro-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-5-(trifluoromethyl)isoquinoline

The mixture of3-chloro-5-iodo-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]isoquinoline(100 mg, 221 umol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (211mg, 1.10 mmol) and CuI (4.18 mg, 22.0 umol) in NMP (5 mL) was heated to80° C. for 2 h under N₂ atmosphere. The reaction was diluted with waterand extracted with EA. The organic layer was concentrated and purifiedby preparative TLC (EA:PE=2:1) to give product 40 mg as a light-yellowsolid.

Analytical Data: LC-MS: (ES, m/z)=393 [M+1].

Example C15: Synthesis of2-(6-chloro-1-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridin-4-yl)propan-1-ol

Step 1: Synthesis of6-chloro-4-iodo-1-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridine

The mixture of 1,6-dichloro-4-iodo-2,7-naphthyridine (300 mg, 923 μmol),(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidine (Example A4, 179 mg,1.10 mmol) and TEA (186 mg, 1.84 mmol) in IPA (15 mL) was stirred at100° C. for 3 h. The mixture was diluted with EA and washed with brine.The organic layer was dried with Na₂SO₄ and concentrated under vacuum.The residue was purified by TLC (PE:EA=1:1). This resulted in 300 mg(72.1%) the title compound as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=452 [M+1].

Step 2: Synthesis of2-(6-chloro-1-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridin-4-yl)prop-2-en-1-ol

Into a 50-mL sealed tube was placed6-chloro-4-iodo-1-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-2,7-naphthyridine(200 mg, 663 μmol), 2-(4,4,5,5-tetrameth (122 mg, 663 μmol), K₂CO₃ (122mg, 884 μmol) and Pd(dppf)Cl₂ (64.6 mg, 88.3 μmol) in dioxane (20 mL)and H₂O (4 mL) under N₂ atmosphere. The resulting solution was stirredat 85° C. for 6 h. The mixture was diluted with EA and washed withbrine. The organic layer was dried with Na₂SO₄ and concentrated undervacuum. The residue was purified by Flash Column Silica-CS(DCM:MeOH=10:1). This resulted in 150 mg (89.2%) of the title compoundas a white solid.

Analytical Data: LC-MS: (ES, m/z)=382 [M+1].

Step 3: Synthesis of2-(6-chloro-1-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridin-4-yl)propan-1-ol

To a solution of2-{6-chloro-1-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-2,7-naphthyridin-4-yl}prop-2-en-1-ol(100 mg, 261 μmol) in EA (30 mL) was added PtO₂ (29.5 mg, 130 μmol).Then the mixture was hydrogenated under hydrogen balloon at rt for 1 h.The mixture was filtrated and concentrated. The residue was purified byTLC (DCM:MeOH=10:1). This resulted in 110 mg of the title compound as ayellow solid.

Analytical Data: LC-MS: (ES, m/z)=384 [M+1].

Example C16: Synthesis of3-chloro-5,7-difluoro-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline

Step 1: Synthesis of 3-chloro-5,7-difluoroisoquinolin-8-ol

To the solution of 3-chloro-5,7-difluoro-8-methoxy-isoquinoline (300 mg,1.31 mmol, 1 equiv.) in DCM (5 mL) was added BBr₃ (982 mg, 3.92 mmol, 3equiv.) at −78° C., then the mixture was stirred at 25° C. for 2 h. Themixture was quenched by 10 mL of water, some solid precipitated. Thesolid was collected by filtration, washed with 10 mL of water. Thisresulted in 0.22 g (77%) of the title compound as a brown solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.645 min, LCMS: m/z=215.8 [M+1].

Step 2: Synthesis of 3-chloro-5,7-difluoroisoquinolin-8-yltrifluoromethanesulfonate

The mixture of 3-chloro-5,7-difluoro-isoquinolin-8-ol (200 mg, 923 μmol,1 equiv),1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(994 mg, 2.78 mmol, 3 equiv) and TEA (282 mg, 2.78 mmol, 3 equiv) in DCM(5 mL) was stirred at 20° C. for 2 h. The mixture was concentrated, theresidue was purified by silica gel chromatography (from PE toPE/EA=50/1). This resulted in 0.26 g (76%) of the title compound as awhite solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.966 min, LCMS: m/z=348.0 [M+1].¹H NMR (400 MHz, DMSO-d₆) δ=9.30 (s, 1H), 8.33 (dd, J=9.6, 10.4 Hz, 1H),8.28 (s, 1H).

Step 3: Synthesis of3-chloro-5,7-difluoro-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline

To the mixture of (3-chloro-5,7-difluoro-8-isoquinolyl)trifluoromethanesulfonate (140 mg, 403 μmol, 1 equiv),3-(methylsulfonylmethyl)azetidine (159 mg, 604 μmol, 1.50 equiv, TFAsalt) and Cs₂CO₃ (393 mg, 1.21 mmol, 3 equiv.) in toluene (1 mL) wasadded (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (23.2 mg, 40.3μmol, 0.1 equiv.), BINAP (201 mg, 322 μmol, 0.8 equiv.) and Pd(OAc)₂(18.1 mg, 80.5 μmol, 0.2 equiv), the mixture was degassed and purgedwith N₂ for 3 times, and then the mixture was stirred at 90° C. for 2 h.The reaction mixture was filtered and concentrated under reducedpressure to give a residue. The residue was purified by silica gelchromatography (Petroleum ether: Ethyl acetate=20:1 to 1:1). Thisresulted in 10 mg (7%) of the title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z): RT=0.900 min, LCMS: m/z=347.1 [M+1].¹H NMR (400 MHz, CDCl₃) δ=9.22 (s, 1H), 7.81 (s, 1H), 4.72-4.65 (m, 1H),4.30-4.25 (m, 1H), 3.45-3.30 (m, 6H).

Example 1, Compound 55: Synthesis of(3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-3-methylpiperidin-4-ol

Step 1: Synthesis of3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

The mixture of Cs₂CO₃ (8.21 g, 25.2 mmol),3-(methanesulfonylmethyl)azetidin-1-ium trifluoromethanesulfonate (6.91g, 23.1 mmol), 8-bromo-3-chloro-5-(propan-2-yl)isoquinoline (fromExample C4, 6.0 g, 21.0 mmol) and XantPhos Pd G3 (1.86 g, 2.10 mmol) indioxane (100 mL) was stirred at 100° C. for 16 h under N₂ atmosphere.The mixture was diluted with EA (200 mL) and washed with brine. Theorganic layer was dried over Na₂SO₄ and concentrated under vacuum. Theresidue was purified by FLASH (DCM:MeOH=30:1) to afford 5.0 g (67%) ofthe title compound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=353 [M+1].

Step 2: Synthesis of(3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-3-methylpiperidin-4-ol

Cs₂CO₃ (3.81 g, 11.7 mmol) was added to C-Phos (627 mg, 1.07 mmol,2-Dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)biphenyl),Pd₂(dba)₃.CHCl₃ (1.42 g, 1.07 mmol),3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline(3.8 g, 10.7 mmol) and(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (2.64g, 11.7 mmol from Example B1) in dioxane (100 mL). The mixture wasstirred at 100° C. for 16 h under N₂ atmosphere. The mixture was dilutedwith EA (500 mL) and washed with brine. The organic layer was dried overNa₂SO₄ and concentrated under vacuum. The crude product was purified byPrep-HPLC Column: XBridge Prep OBD C18 Column 30×150 mm 5 um; MobilePhase A: Water (10 MMOL/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60mL/min; Gradient: 41% B to 90% B in 10 min; 254; 220 nm to get 2.80 g(70%) of the title compound as a yellow solid.

Example 2, Compound 52: Synthesis of(3S,4R)-1-(4-(5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-olor(3R,4S)-1-(4-(5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol

To a solution of3-chloro-8-[3-(methanesulfonylmethyl)azetidin-1-yl]-5-(propan-2-yl)isoquinoline(70 mg, 0.1983 mmol, from Step 1 of Example 1) in 1,4-dioxane was addedcis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol (44.4 mg, 0.1983mmol, peak 1 from Example B10), Cs₂CO₃ (193 mg, 0.59 mmol) and AllylBrettPhos PdOTf (16.5 mg, 19.7 umol). The mixture was stirred at 100° C.for 2 h under N₂ atmosphere. The reaction mixture was cooled to rt anddiluted with 20 mL of water. The resulting solution was extracted with2×20 mL of EA and the organic layers combined. The resulting mixture waswashed with 20 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude product was purified by Prep-HPLCwith the following conditions: Column: XBridge Prep OBD C18 Column30×150 mm Sum; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile PhaseB: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min; 254;220 nm; Rt: 7.17 min. This resulted in 35 mg (32.7%) of the titlecompound as yellow solid.

Example 3, Compound 111: Synthesis of(3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-3-methylpiperidin-4-ol

Step 1: Synthesis of3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline

To a solution of 8-bromo-3-chloro-5-(propan-2-yl)isoquinoline (9 g, 31.6mmol, from Example C4) in 1,4-dioxane (130 mL) was added(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidine (5.15 g, 31.6 mmol,from Example A4), Cs₂CO₃ (20.6 g, 63.2 mmol) and XantphosPd G4 (1.51 g,1.58 mmol) under nitrogen. The mixture was stirred at 100° C. for 3 hunder nitrogen. The reaction mixture was cooled to rt and diluted with300 mL of water. The resulting solution was extracted with EA, washedwith brine, dried over anhydrous sodium sulfate and concentrated undervacuum. The crude product was purified by silica gel chromatography(0-60% EA in PE) to give 7.2 g (62.6%) of3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinolineas yellow solid.

Analytical Data: LC-MS: (ES, m/z)=367 [M+1].

Step 2: Synthesis of(3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-3-methylpiperidin-4-ol

The mixture of3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(5 g, 13.6 mmol), (3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (3.07 g,13.6 mmol, from Example B1), Cs₂CO₃ (8.86 g, 27.2 mmol) and BrettphosPdG3 (616 mg, 0.68 mmol) in dioxane (60 mL) was stirred at 100° C. for 3 hunder nitrogen. The reaction mixture was cooled to rt and diluted withwater. The resulting solution was extracted with EA, washed with brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Thecrude product was purified by silica gel chromatography 0-5% MeOH inDCM. This resulted in 4.6 g (60.7%) of the title compound as yellowsolid.

Example 4, Compound 64: Synthesis ofN-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine

Into a 8-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, was placed3-chloro-5-isopropyl-8-[3-(methanesulfonylmethyl)azetidin-1-yl]isoquinoline(30 mg, 0.085 mmol, 1 equiv. from step 1 of Example 1),2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-amine (19.24 mg,0.085 mmol, 1 equiv., from Example B33), BrettPhos Pd G3 (7.71 mg, 0.009mmol, 0.1 equiv.), Cs₂CO₃ (55.40 mg, 0.170 mmol, 2 equiv.) in dioxane (2mL). The resulting solution was stirred for 3 h at 110° C. The reactionwas then quenched by the addition of 1 mL of water. The solids werefiltered out. The resulting solution was extracted with 3×5 mL of EAconcentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (15:1). The crude product waspurified by Prep-HPLC with the following conditions: Column: XBridgeShield RP18 OBD Column 19*250 mm, 10 um; Mobile Phase A: Water (10mmol/L NH₄HCO_(3+0.1)% NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 25mL/min; Gradient: 30% B to 57% B in 9 min; 254/210 nm; Rt: 8.30 min.This resulted in 20 mg (43.35%) of the title compound as a light-yellowsolid.

Example 5, Compound 117: Synthesis of(3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-ol

To a solution of3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(28 g, 76.3 mmol, from step 1 of Example 3),(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (17.2g, 76.3 mmol, peak 1 from Example B12), Cs₂CO₃ (49.8 g, 152 mmol),C-phos (4.27 g, 9.15 mmol,2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)biphenyl) andPd₂(dba)₃ (3.94 g, 3.81 mmol) in dioxane (400 mL) was heated to 100° C.for 16 h under N₂ atmosphere. The mixture reaction was filtered and thefiltrate was concentration under vacuum. The residue was applied onto asilica gel column with EA/PE (2:1) to give product 28.8 g (67%) as alight-yellow solid.

Example 6, Compound 118: Synthesis of(3R,4S)-3-fluoro-1-(4-(5-isopropyl-8-02R,35)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-ol

To a solution of3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(300 mg, 0.82 mmol, from step 1 of Example 3),(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (185mg, 0.82 mmol, peak 2 from Example B12), Cs₂CO₃ (533 mg, 1.64 mmol),C-phos (45 mg, 0.98 mmol,2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)biphenyl) andPd2(dba)3 (39 mg, 0.38 mmol) in dioxane (5 mL) was heated to 100° C. for16 h under N₂ atmosphere. The mixture reaction was filtered and thefiltrate was concentration under vacuum. The residue was purified byPrep-HPLC with following conditions: Column: XBridge Prep OBD C18Column, 30×150 mm 5 um; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35 B to60 B in 7 min; 254; 220 nm to give 260 mg (57%) of the title compound aspale-yellow solid.

Example 7, Compound 63: Synthesis ofN-(2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine

Into a 8-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, was placed3-chloro-5-isopropyl-8-[3-(methanesulfonylmethyl)azetidin-1-yl]isoquinoline(30 mg, 0.085 mmol, 1 equiv., from step 1 of Example 1),2-[(3R,4S)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-amine (19.24 mg,0.085 mmol, 1 equiv., from Example B32), BrettPhos Pd G3 (7.71 mg, 0.009mmol, 0.10 equiv.) and Cs₂CO₃ (55.40 mg, 0.170 mmol, 2 equiv.) indioxane (2 mL). The resulting solution was stirred for 3 hr at 110° C.The reaction was concentrated and the residue was applied onto Prep-TLCwith DCM/MeOH (15:1) and further purified by Prep-HPLC with thefollowing conditions: Column: XBridge Shield RP18 OBD Column 19*250 mm,10 um; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1% NH₃.H₂O), MobilePhase B: ACN; Flow rate: 25 mL/min; Gradient: 30% B to 57% B in 9 min;254/210 nm; Rt: 8.30 min. This resulted in 20 mg (43.4%) of the titlecompound as a light-yellow solid.

Example 8, Compound 211: Synthesis of(R)-3,3-difluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-olor(S)-3,3-difluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-ol

The mixture of3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(80 mg, 218 μmol, from step 1 of Example 3),(4R)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol or(4S)-1-(4-aminopyrimidin-2-yl)-3,3-difluoro-4-methylpiperidin-4-ol (53.2mg, 218 μmol, peak 2 from Example B13), palladium(1+)2′-amino-1,1′-biphenyl-2-yl xantphos chloride (38.7 mg, 43.6 μmol) andCs₂CO₃ (142 mg, 436 μmol) in diaxone (4 mL) was stirred at rt for 4 h at100° C. under N₂ atmosphere. The resulting solution was concentratedunder vacuum. The crude product was purified by Flash-Prep-HPLC with thefollowing conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm,5 um; Mobile Phase A: Water (0.05% NH₃H₂O), Mobile Phase B: ACN; Flowrate: 60 mL/min; Gradient: 35 B to 65 B in 7 min; 254/220 nm). Theresulted in 57 mg of the title compound as a yellow solid.

Example 9, Compound 92: Synthesis of(3S,4S)-1-(4-(5-isopropyl-8-(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-olor(3R,4R)-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol

Into a 20-mL sealed tube was placed3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(100 mg, 272 μmol, from step 3 of Example 3),trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol (60.9 mg, 272μmol, peak 2 from Example B28), palladium(1+)2′-amino-1,1′-biphenyl-2-yl xantphos chloride (36.2 mg, 40.8 μmol) andcaesium carbonate (177 mg, 544 μmol). The resulting solution was stirredat 100° C. for 16 h. The resulting solution was concentrated undervacuum. The residue was purified by Prep-TLC with DCM/MeOH (20:1). Thecrude product was purified by Prep-Flash-HPLC with following conditions(Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 um; Mobile PhaseA: Water (0.05% NH₃H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min;Gradient: 35 B to 51 B in 7 min; 254/220 nm. This resulted in 64.8 mg ofthe title compound as yellow solid.

Example 10, Compound 150: Synthesis ofN-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-1-isopropyl-4-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)pyrido[4,3-d]pyridazin-7-amine

Step 1: Synthesis of7-chloro-1-isopropyl-4-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)pyrido[4,3-d]pyridazine

To a solution of 4,7-dichloro-1-(propan-2-yl)pyrido[3,4-d]pyridazine(170 mg, 702 umol, from Example C3) and TEA (141 mg, 1.4 mmol) in IPA (3mL) was added (2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidine (126mg, 772 umol, from Example A4). The mixture was stirred for 2 h at 100°C. The mixture was concentrated and the residue was purified by Prep-TLCwith PE/EA (10:1). This resulted in 100 mg (39%) of the title compoundas a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=369 [M+1].

Step 2: Synthesis ofN-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-1-isopropyl-4-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)pyrido[4,3-d]pyridazin-7-amine

The mixture of(2R,3S)-1-[7-chloro-1-(propan-2-yl)pyrido[3,4-d]pyridazin-4-yl]-3-(methanesulfonylmethyl)-2-methylazetidine(100 mg, 271 umol),2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-amine (64 mg,284 umol, from Example B33), Brettphos Pd G3 (49 mg, 54.1 umol) andCs₂CO₃ (176 mg, 542 umol) in dioxane was stirred for 2 h at 100° C.under N₂ atmosphere. The mixture was extracted with EA and water. Theorganic layer was dried by Na₂SO₄ and concentrated. The product waspurified by Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 um;Mobile Phase A: Water (0.05% NH₃H₂O), Mobile Phase B: ACN; Flow rate: 60mL/min; Gradient: 35 B to 45 B in 7 min; 254/220 nm. This resulted in 20mg of the title compound as a white solid.

Example 11, Compound 93: Synthesis of(3S,4R)-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-olor(3R,4S)-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol

Into a 20-mL sealed tube was placed3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(100 mg, 272 μmol, from step 3 of Example 3),cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol (60.9 mg, 272μmol, peak 1 from Example B10), palladium(1+)2′-amino-1,1′-biphenyl-2-yl xantphos chloride (24.1 mg, 27.2 μmol) andcaesium carbonate (177 mg, 544 μmol) in diaxone (5 mL). The resultingsolution was stirred at 100° C. for 16 h. The resulting solution wasconcentrated under vacuum. The residue was purified by Prep-TLC withDCM/MeOH (20:1). The crude product was purified by Prep-Flash-HPLC withfollowing conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm,5 um; Mobile Phase A: Water (0.05% NH₃H₂O), Mobile Phase B: ACN; Flowrate: 60 mL/min; Gradient: 35 B to 50 B in 7 min; 254/220 nm. Thisresulted in 64 mg of the title compound as yellow solid.

Example 12, Compound 103: Synthesis of(3S,4R)-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,6-naphthyridin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-olor(3R,4S)-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,6-naphthyridin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol

Step 1: Synthesis of7-chloro-1-isopropyl-4-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,6-naphthyridine

4-bromo-7-chloro-1-(propan-2-yl)-2,6-naphthyridine (200 mg, 700 μmol,from Example C2), (2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidine(114 mg, 700 μmol, from Example A4), XantPhos Pd G4 (66.4 mg, 70.0 μmol)and caesium carbonate (456 mg, 1.40 mmol) was dissolved in dioxane (4mL). The resulting solution was stirred at 100° C. for 3 h under N₂atmosphere. Then resulting solution was concentrated under vacuum andpurified by Prep-TLC with DCM/MeOH (20:1) to afford 200 mg of the titlecompound as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=368 [M+1].

Step 2: Synthesis of (3S,4R)-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,6-naphthyridin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol

Into a 20-mL sealed tube was placed7-chloro-4-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-1-(propan-2-yl)-2,6-naphthyridine(90 mg, 244 μmol), cis-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol(54.7 mg, 244 μmol, peak 1 from Example B10), palladium(1+)2′-amino-1,1′-biphenyl-2-yl xantphos chloride (21.6 mg, 24.4 μmol) andcaesium carbonate (158 mg, 488 μmol). The resulting solution was stirredat 100° C. for 16 h. The resulting solution was concentrated undervacuum. The residue was purified by Prep-TLC with DCM/MeOH (20:1). Thecrude product was purified by Prep-Flash-HPLC with following conditions(Column: XBridge Shield RP18 OBD Column, 30*150 mm, Sum; Mobile Phase A:Water (0.05% NH₃H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min;Gradient: 30 B to 38 B in 7 min; 254/220 nm. This resulted in 30 mg ofthe title compound as yellow solid.

Example 13, Compound 104: Synthesis of(3S,4S)-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,6-naphthyridin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-olor(3R,4R)-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,6-naphthyridin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol

Into a 20-mL sealed tube was placed7-chloro-4-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-1-(propan-2-yl)-2,6-naphthyridine(50 mg, 135 μmol, from step 1 of Example 12) in dioxane (5 mL),trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol (30.2 mg, 135μmol, peak 1 from Example B28), palladium source (11.9 mg, 13.5 μmol)and cesium carbonate (87.9 mg, 270 μmol). The resulting solution wasstirred at 100° C. for 16 h under N₂ atmosphere. The resulting solutionwas concentrated under vacuum. The residue was purified by Prep-TLC withDCM/MeOH (20:1). The crude product was purified by Prep-Flash-HPLC withfollowing conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm,Sum; Mobile Phase A: Water (0.05% NH₃H₂O), Mobile Phase B: ACN; Flowrate: 60 mL/min; Gradient: 30 B to 40 B in 7 min; 254/220 nm. Thisresulted in 30 mg of the title compound as a yellow solid.

Example 14, Compound 134: Synthesis ofN-(3-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)-1,2,4-triazin-5-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine

The mixture of3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(80 mg, 218 umol, from step 1 of Example 3),3-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]-1,2,4-triazin-5-amine (51.8mg, 228 umol, from Example B73), Brettphos Pd G3 (39.5 mg, 43.6 umol)and Cs₂CO₃ (142 mg, 436 umol) in dioxane (2 mL) was stirred for 2 h at100° C. under N₂ atmosphere. The mixture was concentrated and extractedwith EA and water. The organic layer was dried and concentrated. Theresidue was purified by Column: XBridge Prep OBD C18 Column 30×150 mmSum; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate:60 mL/min; Gradient: 25% B to 50% B in 7 min; 254/220 nm; Rt: 6.07 min.This resulted in 20 mg of the title compound as a yellow solid.

Example 15, Compound 135: Synthesis of(3R,4S)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-ol

Step 1: Synthesis of6-chloro-4-isopropyl-1-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridine

The mixture of 1,6-dichloro-4-isopropyl-2,7-naphthyridine (480 mg, 2.0mmol, from Example C1),(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine (320 mg, 2.0 mmol,from Example A4) and TEA (400 mg, 4.0 mmol) in IPA (2 mL) was stirredovernight at 100° C. The solvent was removed the residue was purified byPLASH (20% EA in PE) to afford6-chloro-4-isopropyl-1-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridine280 mg as yellow solid.

Analytical Data: LC-MS: (ES, m/z)=368 [M+1].

Step 2: Synthesis of(3R,4S)-3-fluoro-1-(4-(5-isopropyl-8-((2R,35)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-ol

The mixture of6-chloro-1-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-4-(propan-2-yl)-2,7-naphthyridine(100 mg, 271 umol),(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (61mg, 271 umol, peak 2 from Example B12), Brettphos Pd G3 (24 mg, 27 umol)and Cs₂CO₃ (176 mg, 542 umol) in dioxane (5 mL) was stirred at 120° C.for 3 h under N₂ atmosphere. The reaction was concentrated and theresidue was purified by preparative HPLC (Column: XBridge Prep OBD C18Column, 30×150 mm 5 um; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33 B to39 B in 9 min; 254/220 nm to give the title compound (57 mg) as alight-yellow solid.

Example 16, Compound 136: Synthesis of(3R,4S)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,6-naphthyridin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-ol

The mixture of7-chloro-4-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-1-(propan-2-yl)-2,6-naphthyridine(60 mg, 163 μmol, from Step 1 of Example 12),(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (36.8mg, 163 μmol, peak 2 from Example B12), palladium(1+)2′-amino-1,1′-biphenyl-2-yl xantphos chloride (14.4 mg, 16.3 μmol) andCs₂CO₃ (106 mg, 326 μmop in dioxane (2 mL) was stirred at 100° C. for 16h under N₂ atmosphere. The resulting solution was concentrated undervacuum and the residue was purified by Prep-TLC with DCM/MeOH (20:1).The crude product was further purified by Prep-Flash-HPLC with followingconditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, Sum;Mobile Phase A: Water (0.05% NH₃H₂O), Mobile Phase B: ACN; Flow rate: 60mL/min; Gradient: 33 B to 42 B in 7 min; 254/220 nm. This resulted in 20mg of the title compound as yellow solid.

Example 17, Compound 190: Synthesis of(3S,4R)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropyl-2,7-naphthyridin-3-ylamino)pyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol

Step 1: Synthesis of6-chloro-1-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-4-isopropyl-2,7-naphthyridine

To a solution of (2R,3S)-3-[(ethanesulfonyl)methyl]-2-methylazetidine(300 mg, 1.69 mmol, from Example A7),1,6-dichloro-4-(propan-2-yl)-2,7-naphthyridine (250 mg, 1.03 mmol, fromExample Cl) and TEA (682 mg, 6.76 mmol) in IPA (4 mL) was heated to 100°C. and stirred overnight. The reaction was concentrated and the residuewas purified by preparative TLC (EA:PE=2:1) to afford the title compound(280 mg) as a light-yellow oil.

Analytical Data: LC-MS: (ES, m/z)=382 [M+1].

Step 2: Synthesis of(3S,4R)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropyl-2,7-naphthyridin-3-ylamino)pyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol

The mixture of6-chloro-1-[(2R,3S)-3-[(ethanesulfonyl)methyl]-2-methylazetidin-1-yl]-4-(propan-2-yl)-2,7-naphthyridine(100 mg, 261 umol),(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (59mg, 261 umol, peak 1 from Example B12), Cs₂CO₃ (171 mg, 522 umol) andBrettphos Pd G3 (23.6 mg, 26.1 umol) in dioxane (4 mL) was stirred at120° C. for 3 h under N₂ atmosphere. The reaction was concentrated andthe residue was purified by preparative HPLC (Column: XBridge Prep OBDC18 Column, 19*250 mm, 5 um; Mobile Phase A: Water (10 mmol/LNH₄HCO_(3+0.1)% NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 25 mL/min;Gradient: 43 B to 43 B in 9 min; 254; 220 nm) to give the title compound(21.8 mg) as light-yellow solid.

Example 18, Compound 137: Synthesis of(3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,7-naphthyridin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-ol

The mixture of6-chloro-1-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-4-(propan-2-yl)-2,7-naphthyridine(100 mg, 271 umol, from step 1 of Example 15),(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (61mg, 271 umol, peak 1 from Example B12), Brettphos Pd G3 (24 mg, 27 umol)and Cs₂CO₃ (176 mg, 542 umol) in dioxane (5 mL) was stirred at 120° C.for 3 h under N₂. The reaction was concentrated and the purified bypreparative HPLC (Column: XBridge Prep OBD C18 Column, 30×150 mm 5 um;Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B:ACN; Flow rate: 60 mL/min; Gradient: 33 B to 38 B in 10 min; 254; 220nm) to give the title compound (70.8 mg) as a light-yellow solid.

Example 19, Compound 138: Synthesis of(3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)-2,6-naphthyridin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-ol

The mixture of7-chloro-4-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-1-(propan-2-yl)-2,6-naphthyridine(50 mg, 135 μmol, from step 1 of Example 12),(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (30.5mg, 135 μmol, peak 1 from Example B12), palladium(1+)2′-amino-1,1′-biphenyl2-yl xantphos chloride (23.9 mg, 27.0 μmol) andCs₂CO₃ (87.9 mg, 270 μmol) in dioxane (2 mL) was stirred at 100° C. for2 h under N₂ atmosphere. The resulting solution was concentrated and theresidue was purified by Prep-Flash-HPLC with following conditions(Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 um; Mobile PhaseA: Water (0.05% NH₃H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min;Gradient: 37 B to 43 B in 7 min; 254/220 nm). This resulted in 20 mg ofthe title compound as yellow-green solid.

Example 20, Compound 177: Synthesis of(3S,4S)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropylisoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-olor(3R,4R)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropylisoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol

Step 1: Synthesis of3-chloro-8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropylisoquinoline

The mixture of 8-bromo-3-chloro-5-(propan-2-yl)isoquinoline (200 mg, 702umol, from Example C4),(2R,3S)-3-[(ethanesulfonyl)methyl]-2-methylazetidine (149 mg, 842 umol,from Example A7), Xantphos Pd G2 (62.3 mg, 70.2 umol) and Cs₂CO₃ (458mg, 1.40 mmol) in dioxane (5 mL) was stirred at 100° C. for 16 h underN₂. The reaction was concentrated and purified by preparative TLC(EA:PE=2:1) to give product 160 mg as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=381 [M+1].

Step 2: Synthesis of(3S,4S)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropylisoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-olor(3R,4R)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropylisoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol

The mixture of3-chloro-8-[(2R,3S)-3-[(ethanesulfonyl)methyl]-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(80 mg, 210 umol),trans-1-(4-aminopyrimidin-2-yl)-4-methoxypiperidin-3-ol (47 mg, 210umol, peak 1 from Example B28), Cs₂CO₃ (137 mg, 420 umol), C-Phos (9.8mg, 21 umol,2-Dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)biphenyl) andPd₂(dba)₃ (12 mg, 10.5 umol) in dioxane (4 mL) was heated to 100° C. for16 h under N₂. The reaction was concentrated and purified by preparativeHPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 um; MobilePhase A: Water (0.05% NH₃H₂O), Mobile Phase B: ACN; Flow rate: 60mL/min; Gradient: 40 B to 48 B in 7 min; 254/220 nm) to give the titlecompound 62 mg as a light-yellow solid.

Example 21, Compound 228: Synthesis of2-((3R,4S)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)piperidin-4-yloxy)ethanol

Into a 8-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, was placed2-[[(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yl]oxy]ethanol(50 mg, 0.195 mmol, 1 equiv. from Example B51),3-chloro-5-isopropyl-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]isoquinoline(71.58 mg, 0.195 mmol, 1 equiv. from step 1 of Example 3), Cs₂CO₃(127.53 mg, 0.390 mmol, 2 equiv.) and Brettphos Pd G3 (17.69 mg, 0.020mmol, 0.1 equiv) in dioxane (3 mL). The resulting solution was stirredfor 3 h at 100° C. The reaction was concentrated and the residue waspurified by Prep-HPLC with following condition: Column: XBridge PrepPhenyl OBD Column, 5 um, 19*250 mm; Mobile Phase A: Water (10 MMOL/LNH₄HCO_(3+0.1)% NH₃.H₂O), Mobile Phase B: MeOH-HPLC; Flow rate: 25mL/min; Gradient: 63 B to 67 B in 11 min; 254; 220 nm; This resulted in20 mg (17.47%) of the title compound as a light-yellow solid.

Example 22, Compound 229: Synthesis of2-((3S,4R)-3-fluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)piperidin-4-yloxy)ethanol

Into a 8-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, was placed2-[[(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yl]oxy]ethanol(50.00 mg, 0.195 mmol, 1 equiv. from Example B52),3-chloro-5-isopropyl-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]isoquinoline(71.58 mg, 0.195 mmol, 1 equiv. from step 1 of Example 3), Cs₂CO₃(127.53 mg, 0.390 mmol, 2 equiv.) and Brettphos Pd G3 (17.69 mg, 0.020mmol, 0.1 equiv.) in dioxane (3 mL). The resulting solution was stirredfor 3 hr at 100° C. The reaction was concentrated and the residue waspurified by Prep-HPLC with following condition: Column: XBridge PrepPhenyl OBD Column, 5 um, 19*250 mm; Mobile Phase A: Water (10 mmol/LNH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: MeOH-HPLC; Flow rate: 25 mL/min;Gradient: 63 B to 66 B in 11 min; 254; 220 nm; This resulted in 10 mg(8.74%) of the title compound as a light-yellow solid.

Example 23, Compound 232: Synthesis of(3S,4S)-5,5-difluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-olor(3R,4R)-5,5-difluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol

A mixture of3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(69.7 mg, 190 μmol, 1 equiv., from step 1 of Example 3),cis-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxypiperidin-3-ol (49.4mg, 190 μmol, 1 equiv., peak 2 from Example B54), BrettPhos Pd G3 (17.1mg, 19.0 μmol, 0.1 equiv.) and Cs₂CO₃ (123 mg, 380 μmol, 2 equiv.) indioxane (2 mL) was heated to 100° C. for 3 h under N₂ atmosphere. Aftercooling down to rt, the mixture was concentrated, the residue waspurified by prep-HPLC with following conditions: Column: XBridge PrepOBD C18 Column, 30×150 mm 5 um; Mobile Phase A: Water (0.05% NH₃H₂O),Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 41 B to 61 B in 7min; 254/220 nm; to afford the title compound (50 mg, 44.64%) as ayellow solid.

Example 24, Compound 152: Synthesis ofN-(2-((R)-4-amino-3,3-difluoropiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl(isoquinolin-3-amineorN-(2-((S)-4-amino-3,3-difluoropiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

Step 1: Synthesis of tert-butyl3,3-difluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)piperidin-4-ylcarbamate

Into a 8-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, was placed tert-butylN-[1-(4-aminopyrimidin-2-yl)-3,3-difluoropiperidin-4-yl]carbamate (100mg, 0.304 mmol, 1 equiv., from Example B57),3-chloro-5-isopropyl-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]isoquinoline(111.40 mg, 0.304 mmol, 1 equiv., from step 1 of Example 3), Cs₂CO₃(198.47 mg, 0.607 mmol, 2 equiv.) and Brettphos Pd G3 (27.52 mg, 0.030mmol, 0.1 equiv.) in dioxane (3 mL). The resulting solution was stirredfor 3 hr at 100° C. The mixture was concentrated and the residue waspurified by Prep-TLC (5% MeOH in DCM). This resulted in 100 mg (49.9%)of the title compound as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=660 [M+1].

Step 2: Synthesis ofN-(2-((R)-4-amino-3,3-difluoropiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amine

The solution of tert-butylN-[3,3-difluoro-1-[4-([5-isopropyl-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]isoquinolin-3-yl]amino)pyrimidin-2-yl]piperidin-4-yl]carbamate(150 mg, 0.227 mmol, 1 equiv.) in DCM (5.00 mL)/TFA (1 mL) was stirredfor 3 h at rt. The resulting mixture was concentrated and the residuewas purified by Prep-TLC (5% MeOH in DCM) to afford 80 mg (62.9%) ofN-[2-(4-amino-3,3-difluoropiperidin-1-yl)pyrimidin-4-yl]-5-isopropyl-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]isoquinolin-3-amineas red oil, which was further separated by Chiral-HPLC to afford theN-(2-((R)-4-amino-3,3-difluoropiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amineorN-(2-((S)-4-amino-3,3-difluoropiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine(peak 2, 10 mg) as pale-yellow solid.

Example 25, Compound 194: Synthesis of(3S,4R)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropyl-2,6-naphthyridin-3-ylamino)pyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol

Step 1: Synthesis of7-chloro-4-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-1-isopropyl-2,6-naphthyridine

The mixture of 4-bromo-7-chloro-1-(propan-2-yl)-2,6-naphthyridine (150mg, 525 umol, from Example C2),(2R,3S)-3-[(ethanesulfonyl)methyl]-2-methylazetidine (111 mg, 630 umol,from Example A7), Cs₂CO₃ (399 mg, 1.04 mmol) and Xantphos Pd G4 (83.9mg, 52.5 umol) in dioxane (3 mL) was stirred overnight at 100° C. underN₂ atmosphere. The reaction mixture was diluted with water, extractedwith EA and washed with brine. The organic layer was dried, filtered,evaporated and purified by column chromatography (DCM:MeOH=25:1) toafford the title compound (170 mg, 85.0%) as a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=382 [M+1].

Step 2: Synthesis of(3S,4R)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropyl-2,6-naphthyridin-3-ylamino)pyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol

The mixture of7-chloro-4-[(2R,3S)-3-[(ethanesulfonyl)methyl]-2-methylazetidin-1-yl]-1-(propan-2-yl)-2,6-naphthyridine(75 mg, 196 umol),(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (44.3mg, 196 umol, peak 1 from Example B12), Cs₂CO₃ (127 mg, 392 umol) andBrettPhos Pd G3 (17.7 mg, 19.6 umol) in dioxane (3 mL) was stirred at110° C. for 4 h. The reaction mixture was diluted with water, extractedwith EA and brine. The organic layer was dried, filtered, evaporated andpurified by column chromatography (DCM:MeOH=10:1) and followed byPrep-HPLC to afford the title compound (41.3 mg, 36.8%) as a yellowsolid.

Example 26, Compound 40: Synthesis ofN-(2-((3aR,6aS)-hexahydrofuro[3,4-b]pyrrol-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-amineand Diastereomer

In a 20 mL sealed tube, the mixture of3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(200 mg, 545 umol, from step 1 of Example 3),2-{hexahydro-1H-furo[3,4-b]pyrrol-1-yl}pyrimidin-4-amine (112 mg, 545umol, from Example B61), Cs₂CO₃ (355 mg, 1.09 mmol) and BrettPhos Pd G3(49.4 mg, 54.5 umol) in dioxane (5 mL) was stirred for 5 h at 100° C.under N₂ atmosphere. The reaction mixture was diluted with water,extracted with EA and washed with brine. The organic layer was dried,filtered, evaporated and purified by column chromatography(DCM:MeOH=10:1) and followed by Prep-HPLC to affordN-(2-{hexahydro-1H-furo[3,4-b]pyrrol-1-yl}pyrimidin-4-yl)-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinolin-3-amine(190 mg, 65.0%) as a light-yellow solid. The product was separated byChiral HPLC to afford the title compound (peak 1) and its diastereomeras light-yellow solids.

Example 27, Compound 243: Synthesis of2-((3R,4S)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropylisoquinolin-3-ylamino)pyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol

In a 8-mL sealed tube, the mixture of3-chloro-8-[(2R,3S)-3-[(ethanesulfonyl)methyl]-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(90 mg, 236 umol, from step 1 of Example 20),2-{[(3R,4S)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yl]oxy}ethan-1-ol(60.4 mg, 236 umol, from Example B51), Cs₂CO₃ (153 mg, 472 umol) andBrettPhos Pd G3 (21.4 mg, 23.6 umol) in dioxane (2 mL) was stirred at100° C. for 5 h under N₂ atmosphere. The reaction mixture was dilutedwith water and extracted with EA and washed with brine. The organiclayer was dried, filtered, evaporated and purified by columnchromatography (DCM:MeOH=10:1) followed by Prep-HPLC to afford the titlecompound (39.5 mg, 28.0%) as a yellow solid.

Example 28, Compound 199: Synthesis of(3S,4R)-3-fluoro-1-(4-(5-((S)-1-hydroxypropan-2-yl)-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-olor(3S,4R)-3-fluoro-1-(4-((5-((R)-1-hydroxypropan-2-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-4-methylpiperidin-4-ol

Step 1: Synthesis of2-(3-chloro-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-5-yl)propan-1-ol

To a solution of 2-(8-bromo-3-chloroisoquinolin-5-yl)propan-1-ol (300mg, 0.9980 mmol, from Example C5) in 1,4-dioxane was added(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidine (162 mg, 0.998 mmol,from Example A4), Cs₂CO₃ (648 mg, 1.99 mmol) and BINAP Pd G3 (93 mg,0.0998 mmol). The mixture was stirred for 3 h at 100° C. The reactionmixture was cooled to rt. The resulting solution was diluted with waterand extracted with EA. The organic layer was concentrated and purifiedby PrepTLC (5% MeOH in DCM. This resulted in 270 mg (70.6%) of2-{3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]isoquinolin-5-yl}propan-1-olas a yellow solid.

Analytical Data: LC-MS: (ES, m/z)=383 [M+1].

Step 2: Synthesis of(3S,4R)-3-fluoro-1-(4-(5-((S)-1-hydroxypropan-2-yl)-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-ol

To a solution of2-{3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]isoquinolin-5-yl}propan-1-ol(220 mg, 0.5745 mmol) in 1,4-dioxane was added(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-4-methylpiperidin-4-ol (129mg, 0.5745 mmol, peak 1 from Example B12), Cs₂CO₃ (371 mg, 1.14 mmol)and XantPhos Pd G2 (25.5 mg, 0.02872 mmol). The mixture was stirred for3 h at 100° C. under nitrogen. The reaction mixture was cooled to rt,diluted with water and extracted with EA. The resulting mixture waswashed brine, dried and concentrated under vacuum. This resulted in 200mg (60.7%) of(3S,4R)-3-fluoro-1-(4-{[5-(1-hydroxypropan-2-yl)-8-((2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl)isoquinolin-3-yl]amino}pyrimidin-2-yl)-4-methylpiperidin-4-olas a yellow solid, which was further separated by chiral-HPLC to afford(3S,4R)-3-fluoro-1-(4-(5-((S)-1-hydroxypropan-2-yl)-8-((2R,3S)-2-methyl-3-(methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)-4-methylpiperidin-4-oland(3S,4R)-3-fluoro-1-(4-((5-((R)-1-hydroxypropan-2-yl)-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-4-methylpiperidin-4-ol(peak 1, 70 mg) as yellow solid.

Example 29, Compound 244: Synthesis of2-((3S,4R)-1-(4-(8-((2R,3S)-3-(ethylsulfonylmethyl)-2-methylazetidin-1-yl)-5-isopropylisoquinolin-3-ylamino)pyrimidin-2-yl)-3-fluoropiperidin-4-yloxy)ethanol

In a 8-mL sealed tube, the mixture of3-chloro-8-[(2R,3S)-3-[(ethanesulfonyl)methyl]-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(90 mg, 236 umol, from step 1 of Example 20),2-{[(3S,4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-yl]oxy}ethan-1-ol(60.4 mg, 236 umol, from Example B52), Cs₂CO₃ (153 mg, 472 umol) andBrettPhos Pd G3 (21.4 mg, 23.6 umol) in dioxane (2 mL) was stirred at100° C. for 5 h under nitrogen atmosphere. The reaction mixture wasdiluted with water, extracted with EA and washed with brine. The organiclayer was dried, filtered, evaporated and purified by columnchromatography (DCM:MeOH=20:1) followed by Prep-HPLC to afford the titlecompound (50.4 mg, 35.7%) as a yellow solid.

Example 30, Compound 251 and 252: Synthesis of2-((R)-3,3-difluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)piperidin-4-yloxy)ethanoland2-((S)-3,3-difluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)piperidin-4-yloxy)ethanol

Into a 40-mL sealed tube was placed3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(900 mg, 2.45 mmol, from step 1 of Example 3) in dioxane (10 mL), wasaddedrac-2-{[1-(4-aminopyrimidin-2-yl)-3,3-difluoropiperidin-4-yl]oxy}ethan-1-ol(671 mg, 2.45 mmol, from Example B69), Cs₂CO₃ (1.59 g, 4.90 mmol) andC-Phos (427 mg, 980 μmol,2-Dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)biphenyl) andPd(dba)₂.CHCl₃ (1.01 g, 980 μmol) under N₂. The resulting solution wasstirred at 110° C. for 3 h. The mixture was diluted with EA and washedwith brine. The organic layer was dried with Na₂SO₄ and concentratedunder vacuum. The residue was purified by Flash Column Silica-CS (DCM:MeOH=1:0 to 10:1). And this resulted in 1 g (67.5%) of2-({3,3-difluoro-1-[4-({8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinolin-3-yl}amino)pyrimidin-2-yl]piperidin-4-yl}oxy)ethan-1-ol a yellow solid, which was furtherseparated by Prep-Chiral-HPLC to afford 400 mg (40%) of2-((R)-3,3-difluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)piperidin-4-yloxy)ethanolor2-((S)-3,3-difluoro-1-(4-(5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl)isoquinolin-3-ylamino)pyrimidin-2-yl)piperidin-4-yloxy)ethanolas a yellow solid.

Example 31, Compound 146: Synthesis of(3S,4S,5R)-5-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-4-methoxypiperidin-3-oland(3R,4R,5S)-5-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol

Into a 25-mL round-bottom flask was placed3-chloro-5-isopropyl-8-[3-(methylsulfonylmethyl)azetidin-1-yl]isoquinoline (5.10 mg, 14.5 μmol, 1 equiv),(3S,4S,5R)-1-(4-aminopyrimidin-2-yl)-5-fluoro-4-methoxy-piperidin-3-oland(3R,4R,5S)-1-(4-aminopyrimidin-2-yl)-5-fluoro-4-methoxy-piperidin-3-ol(3.5 mg, 14.5 μmol, 1 equiv.), BrettPhos (Pd, G4) (1.33 mg, 1.44 μmol,0.100 equiv), BrettPhos (1.55 mg, 2.89 μmol, 0.20 equiv) and KOAc (7.09mg, 72.2 μmol, 5.00 equiv), and dioxane (1 mL). The resulting solutionwas stirred at 100° C. for 5 h under N₂ atmosphere. The mixture wasfiltered and concentrated under vacuum. The residue was purified byPrep-HPLC; mobile phase: water (10 mmol/L FA) and ACN (14.0% ACN up to44.0% in 10 min); UV 254/220 nm. This resulted in 1.6 mg (19%) of thetitle compound as a yellow solid.

Example 32, Compound 200: Synthesis of(3R,4S,5S)-3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-5-methoxypiperidin-4-oland(3S,4R,5R)-3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-5-methoxypiperidin-4-ol

Into a 25-mL round-bottom flask was placed3-chloro-5-isopropyl-8-[(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl]isoquinoline(7.57 mg, 20.6 μmol, 1 equiv.),(3R,4S,5S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-5-methoxy-piperidin-4-oland (3S,4R,5R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-5-methoxy-piperidin-4-ol(5.00 mg, 20.6 μl equiv.), BrettPhos (Pd, G4) (1.90 mg, 2.06 μmol, 0.100equiv.), Cs₂CO₃ (13.4 mg, 41.3 μmol, 2 equiv.), BrettPhos (2.22 mg, 4.13μmol, 0.200 equiv.), and DMA (1.5 mL). The resulting solution wasstirred at 100° C. for 3 h under N₂ atmosphere. The mixture was filteredand concentrated under vacuum. The residue was purified by Prep-HPLC;mobile phase; water (10 mmol/L FA) and ACN (17.0% ACN up to 47.0% in 10min); detector, UV 254/220 nm. This resulted in 2.8 mg (24%) of thetitle compound as yellow solid.

Example 33, Compound 198: Synthesis of racemic of(3R,4R,5S)-5-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-4-methoxypiperidin-3-oland(3S,4S,5R)-5-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-4-methoxypiperidin-3-ol

Into a 25-mL round-bottom flask was placed(3R,4R,5S)-1-(4-aminopyrimidin-2-yl)-5-fluoro-4-methoxy-piperidin-3-oland(3S,4S,5R)-1-(4-aminopyrimidin-2-yl)-5-fluoro-4-methoxy-piperidin-3-ol(21.0 mg, 86.7 μmol, 1 equiv.),3-chloro-5-isopropyl-8-[(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl]isoquinoline(31.8 mg, 86.7 μmol, 1 equiv.), BrettPhos (Pd, G4) (7.98 mg, 8.67 μmol,0.1 equiv.), BrettPhos (9.31 mg, 17.3 μmol, 0.2 equiv.), Cs₂CO₃ (56.5mg, 173 μmol, 2 equiv.), and DMA (1.5 mL). The resulting solution wasstirred at 100° C. for 2 h under N₂ atmosphere. The reaction mixture wasfiltered and concentrated under vacuum. The residue was purified byPrep-HPLC; mobile phase: water (10 mmol/L FA) and ACN (20.0% ACN up to50.0% in 10 min); detector, UV 254/220 nm. This resulted in 23 mg (46%)of the title compound as a yellow solid.

Example 34, Compound 147: Synthesis of racemic(3S,4R,5R)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-5-methoxypiperidin-4-oland(3R,4S,5S)-3-fluoro-1-(4-((5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-5-methoxypiperidin-4-ol

Into a 10-mL microwave tube was placed(3S,4R,5R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-5-methoxy-piperidin-4-ol(32.0 mg, 132 μmol, 1 equiv.),3-chloro-5-isopropyl-8-[3-(methylsulfonylmethyl)azetidin-1-yl]isoquinoline(46.6 mg, 132 μmol, 1 equiv.), BrettPhos (Pd, G4) (12.2 mg, 13.2 μmol,0.1 equiv.), BrettPhos (14.2 mg, 26.4 μmol, 0.2 equiv.), Cs₂CO₃ (86.1mg, 264 μmol, 2 equiv.), DMA (0.7 mL) and dioxane (0.7 mL). Theresulting solution was stirred at 110° C. for 2 h under MW condition.The mixture was filtered and concentrated under vacuum. The residue waspurified by Prep-HPLC; water (10 mmol/L NH₄HCO₃) and ACN (16.0% ACN upto 46.0% in 10 min); detector, UV 254/220 nm. This resulted in 20 mg(27%) of the title compound as yellow solid.

Example 35, Compound 201: Synthesis of(3R,4S,5S)-3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-5-methoxypiperidin-4-ol and(3S,4R,5R)-3-fluoro-1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)-5-methoxypiperidin-4-ol

Into a 25-mL round-bottom flask was placed3-chloro-5-isopropyl-8-[(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl]isoquinoline(7.57 mg, 20.6 μmol, 1 equiv.),(3R,4S,5S)-1-(4-aminopyrimidin-2-yl)-3-fluoro-5-methoxy-piperidin-4-ol(5.00 mg, 20.6 μmol, 1 equiv.), BrettPhos (Pd, G4) (1.90 mg, 2.06 μmol,0.10 equiv.), Cs₂CO₃ (13.5 mg, 41.3 μmol, 2 equiv.), BrettPhos (2.22 mg,4.13 μmol, 0.200 equiv.), and DMA (1.5 mL). The resulting solution wasstirred at 100° C. for 3 h under N₂ atmosphere. The mixture was filteredand concentrated under vacuum. The residue was purified by Prep-HPLC;mobile phase: water (10 mmol/L FA) and ACN (17.0% ACN up to 47.0% in 10min); detector, UV 254/220 nm. This resulted in 2.8 mg (24%) of thetitle compound as yellow solid.

Example 36, Compound 218: Synthesis ofrac-5,5-difluoro-1-[4-[[5-isopropyl-8-[3-(methylsulfonylmethyl)azetidin-1-yl]-3-isoquinolyl]amino]pyrimidin-2-yl]-4-methoxy-piperidin-3-ol

To a solution of3-chloro-5-isopropyl-8-[3-(methylsulfonylmethyl)azetidin-1-yl]isoquinoline(20.3 mg, 57.6 μmol, 1.50 equiv),rac-cis-1-(4-aminopyrimidin-2-yl)-5,5-difluoro-4-methoxy-piperidin-3-ol(10.0 mg, 38.4 μmol, 1 equiv.) and Cs₂CO₃ (37.5 mg, 115 μmol) in dioxane(1 mL) was added BrettPhos (Pd, G4) (3.54 mg, 3.84 μmol, 0.1 equiv.)under N₂, the mixture was stirred at 100° C. for 2 h. The mixture wasfiltered and the filtrate was concentrated in vacuo. The crude waspurified with prep-HPLC [column: Waters Xbridge 150*25 mm*5 um; mobilephase: [water (10 mM NH4HCO3)-ACM; B %: 26%-59%, 11 min]. This resultedin 20 mg (94%) of the title compound as an orange solid.

Example 37, Compound 226: Synthesis of(3R,4S)-1-[4-[[5-isopropyl-8-[3-(methylsulfonylmethyl)azetidin-1-yl]-3-isoquinolyl]amino]pyrimidin-2-yl]-4-(2-methoxyethoxy)piperidin-3-oland(3S,4R)-1-[4-[[5-isopropyl-8-[3-(methylsulfonylmethyl)azetidin-1-yl]-3-isoquinolyl]amino]pyrimidin-2-yl]-4-(2-methoxyethoxy)piperidin-3-ol

To a solution of3-chloro-5-isopropyl-8-[3-(methylsulfonylmethyl)azetidin-1-yl]isoquinoline(6.58 mg, 18.6 μmol, 1 equiv), rac(cis)-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol(Example B78, 5.00 mg, 18.6 μmol, 1 equiv.) and Cs₂CO₃ (18.2 mg, 55.9μmol, 3 equiv.) in dioxane (0.5 mL) was added BrettPhos (Pd, G4) (1.72mg, 1.86 μmol, 0.100 equiv.) under N₂, the mixture was stirred at 100°C. for 2 h. The mixture was filtered and concentrated in vacuo. Thecrude was purified with prep-TLC (DCM:MeOH=10:1) and prep-HPLC [column:Xtimate C18 150*40 mm*10 μm; mobile phase: [water (0.05% ammoniahydroxide v/v)-ACN]; B %: 28%-58%, 10 min]. This resulted in 2.0 mg(18%) of the title compound as a yellow solid.

Example 38, Compound 227:(3S,4S)-1-[4-[[5-isopropyl-8-[3-(methylsulfonylmethyl)azetidin-1-yl]-3-isoquinolyl]amino]pyrimidin-2-yl]-4-(2-methoxyethoxy)piperidin-3-olor(3R,4R)-1-[4-[[5-isopropyl-8-[3-(methylsulfonylmethyl)azetidin-1-yl]-3-isoquinolyl]amino]pyrimidin-2-yl]-4-(2-methoxyethoxy)piperidin-3-ol

To a solution of3-chloro-5-isopropyl-8-[3-(methylsulfonylmethyl)azetidin-1-yl]isoquinoline(13.1 mg, 37.2 μmol, 1 equiv.), rac(trans)-1-(4-aminopyrimidin-2-yl)-4-(2-methoxyethoxy)piperidin-3-ol(Example B79, 10.0 mg, 37.2 μmol, 1 equiv.) and Cs₂CO₃ (36.4 mg, 111μmol, 3 equiv.) in dioxane (0.5 mL) was added BrettPhos (Pd, G4) (3.43mg, 3.73 μmol, 0.1 equiv.) under N₂, the mixture was stirred at 100° C.for 2 h. The mixture was filtered and concentrated in vacuo. The crudewas purified with prep-HPLC to afford 6.5 mg (26%) of the title compoundas a yellow solid.

Example 39, Compound 86: Synthesis of(4S,5R)-1-[4-[[5,7-difluoro-8-[3-(methylsulfonylmethyl)azetidin-1-yl]-3-isoquinolyl]amino]pyrimidin-2-yl]-5-fluoro-3,3-dimethyl-piperidin-4-olor(4R,5S)-1-[4-[[5,7-difluoro-8-[3-(methylsulfonylmethyl)azetidin-1-yl]-3-isoquinolyl]amino]pyrimidin-2-yl]-5-fluoro-3,3-dimethyl-piperidin-4-ol

To a solution of3-chloro-5,7-difluoro-8-[3-(methylsulfonylmethyl)azetidin-1-yl]isoquinoline(5.00 mg, 14.4 μmol, 1 equiv),(4S,5R)-1-(4-aminopyrimidin-2-yl)-5-fluoro-3,3-dimethyl-piperidin-4-olor (4R,5S)-1-[4-[[5,7-difluoro-8-[3-(methylsulfonylmethyl)azetidin-1-yl]-3-isoquinolyl]amino]pyrimidin-2-yl]-5-fluoro-3,3-dimethyl-piperidin-4-ol(peak 2 from Example B11, 4.16 mg, 17.3 μmol, 1.20 equiv.) and Cs₂CO₃(14.1 mg, 43.2 μmol, 3 equiv.) in dioxane (0.5 mL) was added BrettPhos(Pd, G4) (1.33 mg, 1.44 μmol, 0.1 equiv.) under N₂, the mixture wasstirred at 100° C. for 2 h. The mixture was diluted with EA (10 mL),filtered through a thin layer of silica and the filtrate wasconcentrated in vacuo. The crude was purified with prep-HPLC [column:Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (10 mMNH₄HCO₃)-ACN]; B %: 25%-55%, 10 min]. This resulted in 2.3 mg (29%) ofthe title compound as a yellow solid.

Example 40, Compound 282: Synthesis ofN-(2-((3S,4R)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

Step 1: Synthesis of tert-butyl(3S,4R)-3-fluoro-4-(methoxy-d3)piperidine-1-carboxylate

NaH (218.90 mg, 9.122 mmol, 2 equiv.) was added to tert-butyl(3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (1000.00 mg, 4.561mmol, 1.00 equiv.) (Pharmablock) in DMF (20 mL) at 0° C. After stirringfor 20 minutes, CD₃I (3305.67 mg, 22.804 mmol, 5 equiv.) was added andthe resulting solution was stirred for 12 hr at rt. Water was added andthe mixture was extracted with EA. The organic layer was washed withbrine, dried and concentrated to afford 1000 mg of product as lightyellow oil.

Step 2: Synthesis of2-((3S,4R)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-amine

TFA (3 mL) was added to tert-butyl(3S,4R)-3-fluoro-4-(methoxy-d3)piperidine-1-carboxylate (1000.00 mg,4.232 mmol, 1.00 equiv.) in DCM (10 mL) and the solution was stirred for2 h at rt. The mixture was concentrated under vacuum and residue wasdissolved in IPA (20 mL), followed by the addition of2-chloropyrimidin-4-amine (480 mg, 3.60 mmol) and TEA (2229.10 mg). Themixture was stirred overnight at 100° C. The mixture was concentratedand the residue was purified by FLASH (5% MeOH in EA) to afford 500 mgof the title compound as a light yellow solid.

Analytical Data: LC-MS: (ES, m/z)=230 [M+1].

Step 3: Synthesis ofN-(2-((3S,4R)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

The mixture of Cs₂CO₃ (1421.09 mg, 4.362 mmol, 2 equiv.),3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(500.00 mg, 2.181 mmol, 1.00 equiv.),2-((3S,4R)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-amine (340mg, 1.48 mmol) and Brettphos Pd (197.69 mg, 0.218 mmol, 0.1 equiv.) indioxane (10 mL) was heated to 100° C. and stirred for 16 h under N₂atmosphere. The mixture was diluted with EA (100 mL) and washed withbrine. The organic layer was dried over Na₂SO₄ and concentrated undervacuum. The crude product was purified by prep-HPLC to afford the titlecompound, 250 mg as yellow solid.

Example 41, Compound 283: Synthesis ofN-(2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

Step 1: Synthesis of tert-butyl(3R,4S)-3-fluoro-4-(methoxy-d3)piperidine-1-carboxylate

NaH (218 mg, 9.08 mmol) was added to tert-butyl(3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (1000 mg, 4.56 mmol)in DMF (20 mL, 22.6 mmol) at 0° C. After stirring for 20 minutes, CD₃I(3.30 g, 22.8 mmol) was added and the solution was stirred at rt for 16h. The reaction was quenched by the addition of 5 mL of water andextracted with EA and washed with brine and concentrated. This isresulted 1140 mg of the title compound as a light-yellow oil.

Step 2: Synthesis of2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-amine

TFA (2 mL) was added to tert-butyl(3R,4S)-3-fluoro-4-(methoxy-d3)piperidine-1-carboxylate (1140 mg, 4.82mmol) in DCM (6 mL) and the solution was stirred for 2 h at rt. Themixture was concentrated under vacuum and residue was dissolved in IPA(20 mL), followed by 2-chloropyrimidin-4- (496 mg, 3.83 mmol) and TEA(0.6 mL). The mixture was stirred overnight at 100° C. The mixture wasconcentrated and the residue was purified by FLASH (5% MeOH in EA) toafford 425 mg of the title compound as a light-yellow solid.

Analytical Data: LC-MS: (ES, m/z)=230 [M+1].

Step 3: Synthesis ofN-(2-((3R,4S)-3-fluoro-4-(methoxy-d3)piperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

The mixture of Cs₂CO₃ (318 mg, 0.9768 mmol),3-chloro-8-[(2R,3S)-3-(methanesulfonylmethyl)-2-methylazetidin-1-yl]-5-(propan-2-yl)isoquinoline(543 mg, 1.47 mmol), 2-[(3R,4S)-3-fluoro- (340 mg, 1.48 mmol) andBrettphos Pd (134 mg, 0.1480 mmol) in dioxane (20 mL) was heated to 100°C. and stirred for 16 hours under N₂ atmosphere. The mixture was dilutedwith EA (100 mL) and washed with brine. The organic layer was dried overNa₂SO₄ and concentrated under vacuum. The crude product was purified byprep-HPLC to get 327.1 mg of the title compound as yellow solid.

Example 42, Compound 122: Synthesis ofN-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

To a solution of2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (18.50 mg,0.082 mmol, 1 equiv., from Example B33),3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline(30 mg, 0.082 mmol, 1 equiv.) and Cs₂CO₃ (53.3 mg, 0.164 mmol, 2 equiv.)in 1,4-Dioxane (0.82 ml) was added BrettPhos Precatalyst (Gen IV) (3.76mg, 4.09 μmol, 0.05 equiv.) under N₂, the mixture was stirred at 90° C.for 16 h. The mixture was filtered and concentrated in vacuo. The crudemixture was purified by reverse phase chromatography (0 to 60%acetonitrile/water containing 0.1% TFA). Pure fractions were combinedand neutralized with saturated sodium bicarbonate solution and thenextracted with 10% MeOH/DCM (5 mL×3). Combined organic phases dried oversodium sulfate, filtered and evaporated to give 17.4 mg of the titlecompound (38%) as a yellow solid.

Example 43, Compound 123: Synthesis ofN-(2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine

To a solution of2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (18.5 mg,0.082 mmol, 1 equiv., from Example B32),3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline(30 mg, 0.082 mmol, 1 equiv.) and Cs₂CO₃ (53.3 mg, 0.164 mmol, 2 equiv.)in 1,4-Dioxane (0.82 ml) was added BrettPhos Precatalyst (Gen IV) (3.76mg, 4.09 μmol, 0.05 equiv.) under N₂, the mixture was stirred at 90° C.for 16 h. The mixture was filtered and concentrated in vacuo. The crudemixture was purified by reverse phase chromatography (0 to 60%acetonitrile/water containing 0.1% TFA). Pure fractions were combinedand neutralized with saturated sodium bicarbonate solution and thenextracted with 10% MeOH/DCM (5 mL×3). Combined organic phases dried oversodium sulfate, filtered and evaporated to give 20.4 mg of the titlecompound (45%) as a yellow solid.

Chiral Chromatography Conditions:

A. Column: AD 20*250 mm, 10 um (Daicel); Mobile Phase: CO2/MeOH (0.2%ammonia in methanol)=60/40; Flow Rate: 80 g/min.

B. Column: CHIRALPAK IC-3, 0.46*5 cm; 3 um; Mobile phase:(Hex:DCM=3:1)(0.1% DEA):EtOH=50:50; Flow Rate: 1.0 ml/min.

C. Column: Chiral-IC 4.6*100 mm, 5 um; Mobile Phase: CO2/IPA (0.1% DEA),Gradient (B %): 10% to 50% in 4.0 min, hold 2.0 min at 50%; Flow: 4.0ml/min.

D. Column: CHIRALPAK IG-3, 0.46*5 cm; 3 um; Mobile phase: MtBE (0.1%DEA): EtOH=70:30; Flow Rate: 1.0 ml/min.

E. Column name: CHIRALPAK AD-3 3*100 mm, 3 um; Mobile Phase: CO2/MeOH(0.1% DEA), 10% to 50% in 4.0 min, hold 2.0 min at 50%; Flow Rate: 2mL/min.

F. Column: CHIRALPAK IE-3, 0.46*5 cm; 3 um; Mobile phase:(Hex:DCM=3:1)(0.1% DEA):IPA=70:30; Flow Rate: 1.0 ml/min.

G. Column: Reg AD Column Size: 0.46*10 cm; 5 um; Mobile phase A: Hex(0.1% DEA) Mobile phase B: Hex (0.1% FA) Mobile phase C: EtOH Mobilephase D: IPA; Flow: 1.0 mL/min.

H. Column: CHIRAL Cellulose-SB4.6*100 mm 3 um; Mobile phase: Hex (0.1%DEA): EtOH=50:50; Flow Rate: 1 ml/min.

I. Column: Lux Cellulose-4, 0.46*5 cm; 3 um; Mobile phase: Hex (8mMNH3): MeOH:MeOH=40:30:30; Flow Rate: 1.0 mL/min.

J. For intermediate stage: Column: CHIRALPAK IA (0.46*15 cm, 5 um);Mobile Phase: CO2/EtOH (0.1% DEA); Flow Rate: 4 mL/min.

K. Column: CHIRALPAK IA-3; Size: 0.46*5 cm; 3 um; Mobile phase:(Hex:DCM=5:1)(0.1% DEA):IPA=80:20; Flow: 1.0 mL/min.

L. Column: CHIRALPAK ID-3, 0.46*5 cm; 3 um; (Hex:DCM=3:1)(0.1%DEA):MeOH=50:50; Flow Rate: 1.0 ml/min.

M. Column: CHIRALPAK IF-3, 0.46*5 cm; 3 um; Mobile phase:(Hex:DCM=1:1)(0.1% DEA):EtOH=92:8; Flow: 1.5 ml/min.

N. Column: CHIRAL Cellulose-SJ 4.6*150 mm, 3 um; Mobile Phase: CO2/MeOH(0.1% DEA); Flow: 4.0 ml/min.

O. For Intermediate: Column name: Chiral-ND 3.0*100 mm, 3 um; MobilePhase: CO2/MeOH (0.1% DEA); Flow: 4.0 ml/min.

P. Column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase:[0.1% NH₃H₂O IPA]; B %: 60%-60%, 3.5 min; 30 min.

Q. Column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um); mobile phase:[0.1% NH3H₂O-MEOH]; B %: 60%-60%, 4.4 min; 25 min.

R. Column: DAICEL CHIRALCEL OJ (250 mm*50 mm, 10 um); mobile phase:[0.1% NH3H2O MEOH]; B %: 60%-60%, 2.2 min.

S. Column: Cellucoat 50×4.6 mm I.D., 3 um, Mobile phase: Phase A forCO2, and Phase B for MeOH+ACN (0.05% DEA); Gradient elution: 60%MeOH+ACN (0.05% DEA) in CO2, Flow rate: 3 mL/min; Detector: PDA; ColumnTemp: 35 C; Back Pressure: 100 Bar.

T. Column: CHIRALPAK IF-3; Size: 0.46*5 cm; 3 um; Mobile phase: MtBE(0.1% DEA): MeOH=93:7; Flow: 1.0 mL/min.

U. Column: CHIRALPAK IF-3; Size: 0.46*5 cm; 3 um; Mobile phase: MtBE(0.1% DEA): MeOH=50:50; Flow: 1.0 mL/min.

V. Column: CHIRALPAK IF-3; Size: 0.46*5 cm; 3 um; Mobile phase:(Hex:DCM=3:1)(0.1% DEA):IPA=50:50; Flow: 1.0 mL/min.

W. CHIRALPAK IF-3; Size: 0.46*5 cm; 3 um; Mobile phase: MtBE (0.1% DEA):MeOH=93:7; Flow: 1.0 mL/min

X. CHIRALPAK IF-3; Size: 0.46*5 cm; 3 um; Mobile phase:(Hex:DCM=3:1)(0.1% DEA):EtOH=70:30; Flow: 1.0 mL/min.

Y. Column: CHIRALPAK IE-3, 0.46*5 cm; 3 um; Mobile phase:(Hex:DCM=3:1)(0.1% DEA):IPA=90:10; Flow Rate: 1.0 ml/min.

Z. Column: CHIRALPAK IC-3, 0.46*5 cm; 3 um; Mobile phase:Hex:DCM=3:1)(0.1% DEA):EtOH=80:20; Flow Rate: 1.0 ml/min

AA. Column: Chiralpak IG-3 50×4.6 mm I.D., 3 um Mobile phase: Phase Afor CO2, and Phase B for MeOH+ACN (0.05% DEA); Gradient elution: 60%MeOH+ACN (0.05% DEA) in CO2 Flow rate: 3 mL/min; Detector: PDA; ColumnTemp: 35 C; Back Pressure: 100 Bar.

BB. For intermediate stage: Column: CHIRAL Cellulose-SB4.6*100 mm 3 um;mobile phase: Hex (0.1% DEA): IPA=70:30 Flow: 1.0 ml/min; Flow 1.000mL/min.

DD. For intermediate stage: Column: CHIRALPAK IC-3, 3*100 mm 3 um;Mobile Phase A: Mobile Phase B: MeOH (0.1% DEA); Flow rate: 2 mL/min.

EE. For intermediate stage: Column: EnantioPak-A1-5(02), 5*25 cm, 5 um;Mobile Phase A: CO2:60, Mobile Phase B: EtOH 0.1% DEA; Flow rate: 2mL/min.

FF. For intermediate stage: Column: CHIRALPAK AD-3 3*100m m, 3 um;Co-Solvent: MeOH (0.1% DEA); Gradient (B %): 10% to 50% in 4.0 min, hold2.0 min at 50%; Back Pressure (psi): 1500.000; Flow: 2 ml/min.

GG. For intermediate stage: Column: CHIRALPAK AD-3 3*100 m m, 3 um;Co-Solvent: MeOH (0.1% DEA); Gradient (B %): 10% to 50% in 4.0 min, hold2.0 min at 50%; Back Pressure (psi): 1500.000; Flow: 2 ml/min.

HH. For intermediate stage: Column: CHIRALPAK IC, 2*25 cm, 5 um; MobilePhase A: CO2, Mobile Phase B: EtOH (8 mmol/L NH3.MeOH)-HPLC; Flow rate:40 mL/min; Gradient: 25% B; 254 nm; Injection Volume: 0.8 m.

II. For intermediate stage: Column: CHIRALPAK IA (4.6*150 mm, 5 um);solvent, CO2/10% MEOH (0.1% DEA); Flow rate, 4 mL/min.

JJ. For intermediate stage: Column: CHIRALPAK IA (4.6*150 mm, 5 um);solvent, CO2/10% MEOH (0.1% DEA); Flow rate, 4 mL/min.

KK. For intermediate stage: Column: Lux 3 um Cellulose-4 4.6*100 mm, 3um Co-Solvent: MeOH (0.1% DEA).

LL. For intermediate stage: Column: CHIRALPAK IC, 2*25 cm, 5 um; MobilePhase A: CO2, Mobile Phase B: EtOH (8 mmol/L NH3.MeOH)-HPLC; Flow rate:40 mL/min; Gradient: 25% B.

MM. For intermediate stage: Column: CHIRALPAK IA (4.6*150 mm, 5 um);Co-Solvent: MEOH(0.1% DEA), Co-Solvent %: 10%; Flow (ml/min): 4.

NN. For intermediate stage: Phenomenex Lux 5 u Cellulose-3, 5*25 cm, 5um; Mobile Phase A: CO₂: 50, Mobile Phase B: MEOH (0.1% DEA): 50; Flowrate: 170 mL/min; 220 nm.

OO. For intermediate stage: CHIRAL Cellulose-SJ (4.6*150 mm, 5 um);Mobile Phase: CO2/MeOH (0.1% DEA); Flow Rate: 4 g/min.

PP. For intermediate stage: CHIRALCEL OJ-3, 4.6*50 mm, 3 um; Co-Solvent:MeOH (0.1% DEA) Gradient (B %): 10% to 50% in 4.0 min, hold 2.0 m in at50%; Back Pressure (psi): 1500.

QQ. For intermediate stage (aminopyrimidine, analogous to example B54):Column: CHIRALPAK IA-3; Size: 3.0*100 mm, 3 um; Co-solvent: MeOH (0.1%DEA); Flow rate 2 mL/min.

Table 1 lists the compounds prepared by the synthetic methods disclosedabove.

TABLE 1 Sepa- ra- tion Con- LC/ di- # Structure MS NMR tions ChemicalName 1

497 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.05 (s, 1H), 8.65(s, 1H), 8.04 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56-6.49(m, 1H), 6.41 (d, 1H, J = 8.1 Hz), 4.39 (t, 2H, J = 7.6 Hz), 3.97 (t,2H, J = 6.9 Hz), 3.75 (dd, 8H, J = 20.1, 5.2 Hz), 3.59 (d, 2H, J = 7.3Hz), 3.48-3.40 (m, 1H), 3.32-3.22 (m, 1H), 3.02 (s, 3H), 1.28 (d, 6H, J= 6.8 Hz) 8-[3- (methane- sulfonylmethyl) azetidin-1-yl]-N-[2-(morpholin-4- yl)pyrimidin-4- yl]-5-(propan-2- yl)isoquinolin-3-amine 2

498 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.14 (s, 1H), 9.00 (s, 1H), 8.51(s, 1H), 8.06 (d, 1H, J = 5.6 Hz), 7.96 (s, 1H), 6.53 (d, 1H, J = 5.7Hz), 4.54 (t, 2H, J = 8.4 Hz), 4.20 (dd, 2H, J = 8.6, 6.2 Hz), 3.72 (dd,8H, J = 11.4, 4.6 Hz), 3.57 (d, 2H, J = 7.4 Hz), 3.23 (dt, 2H, J = 13.7,7.3 Hz), 2.99 (s, 3H), 1.27 (d, 6H, J = 6.8 Hz) 8-[3- (methane-sulfonylmethyl) azetidin-1-yl]-N- [2-(morpholin-4- yl)pyrimidin-4-yl]-5-(propan- 2-yl)-2,7- naphthyridin-3- amine 3

511 1H NMR (300 MHz, 6d- DMSO) δ ppm 10.13 (s, 1H), 9.02 (s, 1H), 8.06(d, 1H, J = 5.6 Hz), 7.98 (s, 1H), 6.51 (d, 1H, J = 5.6 Hz), 4.57 (t,2H, J = 8.4 Hz), 4.22 (dd, 2H, J = 8.6, 6.2 Hz), 3.80 (t, 4H, J = 4.9Hz), 3.60 (d, 2H, J = 7.4 Hz), 3.54-3.23 (m, 2H), 3.01 (s, 3H), 2.41 (t,4H, J = 4.9 Hz), 2.26 (s, 3H), 1.31 (d, 6H, J = 6.8 Hz) 8-[3- (methane-sulfonylmethyl) azetidin-1-yl]-N- [2-(4-methyl- piperazin-1-yl)pyrimidin-4-yl]- 5-(propan-2-yl)- 2,7-naphthy- ridin-3-amine 4

515 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.90 (s, 1H), 9.05 (s, 1H), 8.33(s, 1H), 8.01 (d, 1H, J = 5.6 Hz), 7.48 (t, 1H, J = 7.8 Hz), 7.16 (d,1H, J = 8.1 Hz), 6.51 (dd, 2H, J = 13.6, 6.7 Hz), 4.91 (d, 1H),4.79-4.59 (m, 2H), 4.50- 4.36 (m, 1H), 4.25 (t, 1H, J = 6.2 Hz), 3.74(t, 1H, J = 7.0 Hz), 3.62-3.49 (m, 3H), 3.48- 3.42 (m, 2H), 3.37 (s,3H), 3.01 (s, 3H), 2.94-2.86 (m, 1H), 1.85-1.79 (m, 2H), 1.45 (d, 3H, J= 6.0 Hz), N-{2-[(3R,4S)-3- fluoro-4- methoxypiperidin-1-yl]pyrimidin-4- yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]isoquinolin-3- amine 5

515 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.90 (s, 1H), 9.05 (s, 1H), 8.33(s, 1H), 8.01 (d, 1H, J = 5.7 Hz), 7.48 (t, 1H, J = 7.9 Hz), 7.16 (d,1H, J = 8.1 Hz), 6.51 (dd, 2H, J = 13.3, 6.7 Hz), 4.99 (d, 1H, J = 48.2Hz), 4.79-4.59 (m, 2H), 4.47-4.36 (m, 1H), 4.25 (t, 1H, J = 6.2 Hz),3.74 (t, 1H, J = 7.1 Hz), 3.66-3.39 (m, 4H), 3.37 (s, 3H), 3.30- 3.21(m, 1H), 3.01 (s, 3H), 2.90 (q, 1H, J = 7.0 Hz), 1.92- 1.69 (m, 2H),1.45 (d, 3H, J = 6.0 Hz) N-{2-[(3S,4R)-3- fluoro-4- methoxypiperidin-1-yl]pyrimidin-4- yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]isoquinolin-3- amine 6

516 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.03 (s, 1H), 8.99 (s, 1H), 8.27(s, 1H), 8.05-7.95 (m, 2H), 6.75 (d, 1H, J = 5.8 Hz), 6.46 (d, 1H, J =5.7 Hz), 5.11 (d, 1H, J = 5.4 Hz), 4.74 (d, 1H, J = 48.6 Hz), 4.60 (t,2H, J = 8.5 Hz), 4.25 (dd, 3H, J = 8.9, 6.1 Hz), 3.91-3.73 (m, 2H), 3.59(d, 2H, J = 7.4 Hz), 3.45 (ddd, 1H, J = 23.1, 5.6, 2.8 Hz), 3.38-3.27(m, 2H), 3.00 (s, 3H), 0.98-0.90 (m, 6H) J; Peak 2 (4S,5R)-5-fluoro-1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1- yl]-2,7-naph-thyridin-3-yl} amino)pyrimidin- 2-yl]-3,3- dimethylpiperidin- 4-ol or(4R,5S)-5- fluoro-1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-2,7-naph- thyridin-3-yl} amino)pyrimidin- 2-yl]-3,3- dimethyl-piperidin-4-ol

7

518 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.20 (s, 1H), 9.03 (s, 1H), 8.74(s, 1H), 8.07 (d, 1H, J = 5.7 Hz), 7.99 (s, 1H), 6.55 (d, 1H, J = 5.7Hz), 5.56 (s, 1H), 5.43 (s, 1H), 4.57 (t, 2H, J = 8.4 Hz), 4.22 (dd, 2H,J = 8.6, 6.2 Hz), 4.14 (s, 1H), 3.91 (s, 2H), 3.76 (s, 2H), 3.60 (d, 2H,J = 7.4 Hz), 3.02 (s, 3H), 1.32 (d, 6H, J = 6.8 Hz) B8 N-{2-[cis-3,4-difluoropyrrolidin- 1-yl]pyrimidin-4- yl}-8-[3- (methanesulfonyl-methyl)azetidin-1- yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-amine 8

518 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.20 (s, 1H), 9.03 (s, 1H), 8.69(s, 1H), 8.08 (d, 1H, J = 5.7 Hz), 7.99 (s, 1H), 6.59 (d, 1H, J = 5.7Hz), 5.62 (s, 1H), 5.50 (s, 1H), 4.57 (td, 2H, J = 8.5, 2.4 Hz), 4.22(dd, 2H, J = 8.6, 6.2 Hz), 3.97 (s, 4H), 3.86 (s, 1H), 3.60 (d, 2H, J =7.4 Hz), 3.02 (s, 3H), 1.34 (dd, 6H, J = 9.3, 6.8 Hz) D; Peak 1N-{2-[(3S,4S)-3,4- difluoropyrrolidin- 1-yl]pyrimidin-4- yl}-8-[3-(methanesulfonyl- methyl)azetidin-1- yl]-5-(propan-2- yl)-2,7-naph-thyridin-3-amine or N-{2-[(3R,4R)- 3,4-difluoro- pyrrolidin-1-yl]pyrimidin-4-yl}-8- [3-(methane- sulfonylmethyl) azetidin-1-yl]-5-(propan-2-yl)-2,7-

naphthyridin-3- amine 9

518 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.20 (s, 1H), 9.03 (s, 1H), 8.69(s, 1H), 8.08 (d, 1H, J = 5.7 Hz), 7.99 (s, 1H), 6.59 (d, 1H, J = 5.7Hz), 5.62 (s, 1H), 5.50 (s, 1H), 4.57 (td, 2H, J = 8.4, 2.4 Hz), 4.23(dd, 2H, J = 8.6, 6.2 Hz), 4.08-3.87 (m, 4H), 3.60 (d, 2H, J = 7.4 Hz),3.37-3.32 (m, 2H), 3.02 (s, 3H), 1.34 (dd, 6H, J = 9.3, 6.8 Hz) D; Peak2 N-{2-[(3R,4R)-3,4- difluoropyrrolidin- 1-yl]pyrimidin-4- yl}-8-[3-(methanesulfonyl- methyl)azetidin-1- yl]-5-(propan-2- yl)-2,7-naph-thyridin-3-amine or N-{2-[(3S,4S)- 3,4-difluoro- pyrrolidin-1-yl]pyrimidin-4-yl}-8- [3-(methane- sulfonylmethyl) azetidin-1-yl]-5-(propan-2-yl)-2,7- naphthyridin-3-

amine 10

523 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.86 (s, 1H), 9.01 (s, 1H), 8.85(s, 1H), 7.96 (d, 1H, J = 5.7 Hz), 7.39 (d, 1H, J = 8.0 Hz), 6.44-6.34(m, 2H), 4.36 (t, 2H, J = 7.6 Hz), 3.99-3.73 (m, 4H), 3.62-3.45 (m, 7H),3.30- 3.18 (m, 1H), 3.02 (d, 2H, J = 13.5 Hz), 3.00 (s, 3H), 1.26 (d,6H, J = 6.7 Hz) N-{2-[(3aR,6aS)- hexahydro-1H- furo[3,4-c]pyrrol-5-yl]pyrimidin-4- yl}-8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- amine 11

523 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.78 (s, 1H), 9.01 (s, 1H), 8.82(d, 1H, J = 10.5 Hz), 7.90 (d, 1H, J = 5.6 Hz), 7.39 (d, 1H, J = 7.8Hz), 6.36 (dd, 2H, J = 12.5, 6.8 Hz), 4.88 (s, 1H), 4.64 (d, 1H, J =52.8 Hz), 4.36 (t, 2H, J = 7.6 Hz), 3.94 (t, 2H, J = 6.9 Hz), 3.89-3.74(m, 1H), 3.54 (dd, 4H, J = 19.0, 7.1 Hz), 3.30-3.08 (m, 1H), 3.05-2.87(m, 3H), 2.47-2.39 (m, 1H), 2.13-1.75 (m, 2H), 1.68-1.37 (m, 2H), 1.28(dd, 6H, J = 6.9, 2.2 Hz) D; Peak 2 (1R,4R,5R)-2-[4- ({8-[3-(methane-sulfonylmethyl) azetidin-1-yl]-5- (propan-2-yl) isoquinolin-3-yl}amino)pyrimidin- 2-yl]-2-azabicyclo [2.2.1]heptan-5- ol or (1S,4S,5S)-2-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]-

2-azabicyclo [2.2.1]heptan-5- ol 12

523 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.87 (s, 1H), 9.03 (s, 1H), 8.65(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.40 (d, 1H, J = 8.0 Hz), 6.47 (d,1H, J = 5.7 Hz), 6.39 (d, 1H, J = 8.1 Hz), 4.38 (dd, 4H, J = 14.9, 7.1Hz), 4.25 (d, 2H, J = 12.8 Hz), 3.94 (t, 2H, J = 6.9 Hz), 3.57 (d, 2H, J= 7.3 Hz), 3.45 (p, 1H, J = 6.8 Hz), 3.28-3.20 (m, 1H), 3.11 (d, 2H, J =12.4 Hz), 3.00 (s, 3H), 1.89-1.80 (m, 2H), 1.72 (d, 2H, J = 6.9 Hz),1.27 (d, 6H, J = 6.8 Hz) 8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-N-(2-{8-oxa- 3-azabicyclo [3.2.1]octan-3-yl} pyrimidin-4-yl)-5-(propan-2- yl)isoquinolin-3- amine 13

523 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.87 (s, 1H), 9.03 (s, 1H), 8.65(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.40 (d, 1H, J = 8.0 Hz), 6.47 (d,1H, J = 5.7 Hz), 6.39 (d, 1H, J = 8.1 Hz), 4.38 (dd, 4H, J = 14.9, 7.1Hz), 4.25 (d, 2H, J = 12.8 Hz), 3.94 (t, 2H, J = 6.9 Hz), 3.57 (d, 2H, J= 7.3 Hz), 3.45 (p, 1H, J = 6.8 Hz), 3.28-3.20 (m, 1H), 3.11 (d, 2H, J =12.4 Hz), 3.00 (s, 3H), 1.89-1.80 (m, 2H), 1.72 (d, 2H, J = 6.9 Hz),1.27 (d, 6H, J = 6.8 Hz) (rac)-8-[3- (methanesulfonyl-methyl)azetidin-1- yl]-N-{2-[6-oxa- 3-azabicyclo [3.2.1]octan-3-yl]pyrimidin-4-yl}- 5-(propan-2-yl) isoquinolin-3- amine 14

523 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.91 (s, 1H), 9.05 (s, 1H), 8.76(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.47 (d,1H, J = 5.7 Hz), 6.41 (d, 1H, J = 8.0 Hz), 4.39 (t, 4H, J = 7.2 Hz),4.28 (d, 1H, J = 13.4 Hz), 3.97 (t, 2H, J = 6.9 Hz), 3.79-3.72 (m, 2H),3.59 (d, 2H, J = 7.3 Hz), 3.55-3.44 (m, 1H), 3.31-3.21 (m, 2H),3.09-3.04 (m, 1H), 3.02 (s, 3H), 2.66-2.60 (m, 1H), 1.97-1.91 (m, 2H),1.30 (dd, 6H, J = 6.8, 3.8 Hz) L; Peak 2 N-{2-[(3aR,6aS)- hexahydro-1H-furo[3,4-c]pyrrol- 5-yl]pyrimidin-4- yl}-8-[3- (methanesulfonyl-methyl)azetidin-1- yl]-5-(propan- 2-yl)-2,7-naph- thyridin-3-amine orN-{2- [(3aS,6aR)- hexahydro-1H- furo[3,4-c]pyrrol- 5-yl]pyrimidin-4-yl}-8-[3-

(methanesulfonyl- methyl)azetidin-1- yl]-5-(propan-2- yl)-2,7-naph-thyridin-3-amine 15

524 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.83 (s, 1H), 9.05 (s, 1H), 8.65(s, 1H), 7.99 (d, J = 5.6 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 6.44 (d, J= 5.6 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 4.38 (q, J = 8.0 Hz, 2H),4.35-4.25 (m, 2H), 4.02-3.91 (m, 2H), 3.71 (s, 1H), 3.54-3.38 (m, 6H),3.35-3.25 (m, 1H), 3.32 (s, 3H), 2.93 (s, 3H), 1.95-1.87 (m, 2H),1.52-1.40 (m, 2H), 1.29 (dd, J = 8.0, 3.6 Hz, 6H). (S)-imino((1-(5-isopropyl-3-((2- (4-methoxy- piperidin-1-yl) pyrimidin-4-yl)amino)isoquinolin- 8-yl)azetidin-3- yl)methyl) (methyl)-λ⁶- sulfanone or(R)- imino((1-(5- isopropyl-3-((2- (4-methoxy- piperidin-1-yl)pyrimidin-4-yl)

amino)isoquino- lin-8-yl) azetidin-3-yl) methyl)(methyl)- λ⁶-sulfanone16

524 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.05 (s, 1H), 8.68(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.55 (d,1H, J = 8.1 Hz), 6.45 (d, 1H, J = 5.6 Hz), 4.65 (t, 1H, J = 7.5 Hz),4.18 (p, 1H, J = 6.1 Hz), 3.80 (t, 4H, J = 5.0 Hz), 3.63 (t, 1H, J = 7.2Hz), 3.56 (dd, 1H, J = 14.2, 6.8 Hz), 3.51 (t, 1H, J = 6.9 Hz), 3.50-3.41 (m, 1H), 2.99 (s, 3H), 2.89 (p, 1H, J = 7.3 Hz), 2.41 (t, 4H, J =5.0 Hz), 2.25 (s, 3H), 1.42 (d, 3H, J = 6.0 Hz), 1.29 (d, 6H, J = 6.7Hz) 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-N-[2-(4- methylpiperazin- 1-yl)pyrimidin-4- yl]-5-(propan-2-yl)isoquinolin-3- amine 17

525 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.84 (s, 1H), 9.04 (s, 1H), 8.70(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.1 Hz), 6.44-6.37(m, 2H), 4.43-4.35 (m, 3H), 4.27 (d, 2H, J = 13.0 Hz), 3.97 (t, 2H, J =6.9 Hz), 3.59 (d, 2H, J = 7.4 Hz), 3.48 (dd, 3H, J = 13.1, 7.6 Hz),3.33- 3.24 (m, 1H), 3.02 (s, 3H), 1.60-1.48 (m, 4H), 1.29 (d, 6H, J =6.8 Hz), 1.19 (s, 3H) 1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]-4-methylpiperidin- 4-ol 18

525 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.84 (s, 1H), 9.05 (s, 1H), 8.62(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.45 (d,1H, J = 5.7 Hz), 6.40 (d, 1H, J = 8.1 Hz), 4.70 (d, 1H, J = 5.4 Hz),4.66 (s, 1H), 4.64- 4.52 (m, 1H), 4.39 (td, 2H, J = 7.6, 2.4 Hz),4.02-3.91 (m, 2H), 3.59 (d, 2H, J = 7.4 Hz), 3.49 (p, 1H, J = 6.8 Hz),3.32-3.17 (m, 2H), 3.07 (d, 1H, J = 12.4 Hz), 3.02 (s, 3H), 2.66 (dd,1H, J = 13.1, E; Peak 2 (3S,4S)-1-[4- ({8-[3- (methanesulfonyl-methyl)azetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 3-methyl- piperidin-4-ol or (3R,4R)-1-[4- ({8-[3-(methanesulfonyl- methyl)azetidin-1- yl]-5-(propan-2-

10.6 Hz), 1.95-1.84 (m, 1H), 1.55-1.24 (m, 8H), 0.98 (d, 3H, J = 6.5 Hz)yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methyl- piperidin-4-ol 19

525 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.80 (s, 1H), 9.04 (s, 1H), 8.66(s, 1H), 7.97 (d, 1H, J = 5.6 Hz), 7.40 (d, 1H, J = 8.0 Hz), 6.44-6.36(m, 2H), 4.63 (d, 1H, J = 3.8 Hz), 4.38 (td, 2H, J = 7.6, 2.9 Hz),4.17-3.89 (m, 4H), 3.78 (p, 1H, J = 3.6 Hz), 3.66 (ddd, 1H, 1 = 13.1,9.1, 4.0 Hz), 3.58 (d, 2H, J = 7.4 Hz), 3.55-3.35 (m, 2H), 3.32- 3.20(m, 1H), 3.01 (s, 3H), 1.79-1.60 (m, 2H), 1.28 (t, 6H, J = 6.5 Hz), 0.89(d, 3H, C; Peak 1 (3S,4R)-1-[4-({8- [3-(methane- sulfonylmethyl)azetidin-1-yl]-5- (propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 3-methyl- piperidin-4-ol or (3R,4S)-1-[4- ({8-1,3-(methanesulfonyl- methyl)azetidin-1- yl]-5-(propan-2-

J = 6.8 Hz) yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methyl-piperidin-4-ol 20

525 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.80 (s, 1H), 9.04 (s, 1H), 8.65(s, 1H), 7.97 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.43-6.37(m, 2H), 4.63 (d, 1H, J = 3.9 Hz), 4.38 (td, 2H, J = 7.6, 2.9 Hz),4.12-4.04 (m, 1H), 4.04-3.92 (m, 3H), 3.79 (t, 1H, J = 4.3 Hz), 3.66(ddd, 1H, J = 13.0, 9.1, 4.1 Hz), 3.59 (d, 2H, J = 7.4 Hz), 3.49 (p, 1H,J = 6.8 Hz), 3.42-3.38 (m, 1H), 3.32-3.22 (m, 1H), 3.01 (s, 3H),1.84-1.52 (m, C; Peak 2 (3R,4S)-1-[4-({8- [3-(methane- sulfonylmethyl)azetidin-1-yl]-5- (propan-2-yl) isoquinolin-3-yl} amino)pyrimidin-2-yl]-3-methyl- piperidin-4-ol or (3S,4R)-1-[4- ({8-[3-(methane-sulfonylmethyl) azetidin-1-yl]-5- (propan-2-yl) isoquinolin-3-yl}

3H), 1.29 (t, 6H, J = 6.5 Hz), 0.89 (d, 3H, J = 6.8 Hz) amino)pyrimidin-2-yl]-3-methyl- piperidin-4-ol 21

525 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.79 (s, 1H), 9.04 (s, 1H), 8.71(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.41 (d,2H, J = 6.9 Hz), 4.53 (d, 1H, J = 4.0 Hz), 4.39 (t, 2H, J = 7.6 Hz),3.96 (t, 2H, J = 6.8 Hz), 3.92-3.78 (m, 2H), 3.77- 3.66 (m, 3H), 3.59(d, 2H, J = 7.3 Hz), 3.55-3.44 (m, 1H), 3.02 (s, 3H), 1.97-1.91 (m, 2H),1.77-1.47 (m, 4H), 1.29 (d, 6H, J = 6.7 Hz) (rac)-1-[4-({8-[3-(methanesulfonyl- methyl)azetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl] azepan-4-ol 22

526 1H NMR (300 MHz, 6d- DMSO) δ ppm 10.10 (s, 1H), 9.02 (s, 1H), 8.55(s, 1H), 8.05 (d, 1H, J = 5.6 Hz), 7.99 (s, 1H), 6.48 (d, 1H, J = 5.6Hz), 4.57 (t, 2H, J = 8.4 Hz), 4.38-4.08 (m, 2H), 3.60 (d, 2H, J = 7.4Hz), 3.54-3.37 (m, 6H), 3.31 (s, 4H), 3.01 (s, 3H), 1.93 (d, 2H, J =12.7 Hz), 1.46 (d, 2H, J = 9.2 Hz), 1.31 (d, 6H, J = 6.8 Hz)8-[3-(methane- sulfonylmethyl) azetidin-1-yl]-N- [2-(4-methoxy-piperidin-1-yl) pyrimidin-4-yl]- 5-(propan-2-yl)- 2,7-naph-thyridin-3-amine 23

526 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.47 (s, 1H), 9.10 (s, 1H), 8.71(s, 1H), 8.47 (s, 1H), 7.46 (d, 1H, J = 8.0 Hz), 6.46 (d, 1H, J = 8.1Hz), 4.40 (t, 2H, J = 7.7 Hz), 4.26 (dd, 2H, J = 12.5, 6.2 Hz), 3.98 (t,2H, J = 6.9 Hz), 3.63-3.47 (m, 4H), 3.48 (s, 2H), 3.32-3.28 (m, 1H),3.25 (s, 3H), 3.01 (s, 3H), 2.02-1.89 (m, 2H), 1.51 (qd, 2H, J = 8.6,4.3 Hz), 1.29 (d, 6H, J = 6.7 Hz) 8-[3-(methane- sulfonylmethyl)azetidin-1-yl]-N- [3-(4-methoxy- piperidin-1-yl)- 1,2,4-triazin-5-yl]-5-(propan-2- yl)isoquinolin-3- amine 24

529 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.03 (s, 1H), 8.59(s, 1H), 7.99 (d, 1H, J = 5.7 Hz), 7.39 (d, 1H, J = 8.0 Hz), 6.49 (d,1H, J = 5.8 Hz), 6.39 (d, 1H, J = 8.1 Hz), 5.44 (d, 1H, J = 5.0 Hz),4.52 (t, 3H, J = 17.9 Hz), 4.37 (t, 2H, J = 7.7 Hz), 3.94 (t, 2H, J =6.8 Hz), 3.67-3.37 (m, 4H), 3.28-3.12 (m, 1H), 3.10-2.87 (m, 4H),2.18-2.03 (m, 1H), 1.76-1.54 (m, 1H), 1.27 (dd, 6H, J = 6.8, 5.4 Hz) F;Peak 2 (3S,4S)-4-fluoro- 1-[4-({8-[3- (methanesulfonyl-methyl)azetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl] piperidin-3-ol or (3R,4R)-4-fluoro- 1-[4-({8-[3-(methanesulfonyl- methyl)azetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-

yl}amino) pyrimidin-2-yl] piperidin-3-ol 25

529 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.92 (s, 1H), 9.05 (s, 1H), 8.47(s, 1H), 7.99 (d, 1H, J = 5.7 Hz), 7.35 (d, 1H, J = 7.8 Hz), 6.44 (d,1H, J = 5.7 Hz), 6.33 (d, 1H, J = 7.8 Hz), 5.02 (d, 1H, J = 6.4 Hz),4.85-4.65 (m, 2H), 4.40 (dt, 2H, J = 18.2, 9.8 Hz), 3.96 (t, 2H, J = 6.9Hz), 3.58 (d, 2H, J = 7.4 Hz), 3.55-3.43 (m, 1H), 3.32-3.22 (m, 1H),3.13 (q, 4H, J = 7.5 Hz), 2.51 (s, 3H), 1.83-1.60 (m, 2H), 1.36 (d, 3H,J = 21.2 Hz), 1.25 (t, 3H, J = 7.4 Hz) NN; Peak 1 (3S,4R)-1-{4-[(8-{3-[(ethane- sulfonyl)methyl] azetidin-1-yl}-5- methyliso-quinolin-3-yl) amino]pyrimidin- 2-yl}-3-fluoro-3- methyl- piperidin-4-ol26

529 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.88 (s, 1H), 9.05 (s, 1H), 8.63(s, 1H), 8.01 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.49 (d,1H, J = 5.7 Hz), 6.42 (d, 1H, J = 8.0 Hz), 5.21 (d, 1H, J = 5.4 Hz),4.85 (d, 1H, J = 48.7 Hz), 4.39 (t, 2H, J = 7.6 Hz), 4.29-4.09 (m, 2H),3.97 (t, 2H, J = 6.9 Hz), 3.77-3.63 (m, 1H), 3.59 (d, 2H, J = 7.5 Hz),3.57-3.44 (m, 3H), 3.30- 3.21 (m, 1H), 3.02 (s, 3H), 2.10-1.95 (m, 2H),1.93- H; Peak 1 (3R,4S)-4-fluoro- 1-[4-({8-[3- (methanesulfonyl-methyl)azetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl] piperidin-3-ol or (3S,4R)-4-fluoro- 1-[4-({8-[3-(methanesulfonyl- methyl)azetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-

1.72 (m, 1H), 1.30 (dd, 6H, J = 6.8, 3.3 Hz) yl}amino) pyrimidin-2-yl]piperidin-3-ol 27

529 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.86 (s, 1H), 9.05 (s, 1H), 8.40(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.48 (t, 1H, J = 7.9 Hz), 7.06 (d,1H, J = 8.1 Hz), 6.43 (d, 1H, J = 5.7 Hz), 6.36 (d, 1H, J = 7.6 Hz),5.12 (d, 1H, J = 5.5 Hz), 4.76 (dt, 1H, J = 48.2, 3.7 Hz), 4.46 (t, 2H,J = 7.8 Hz), 4.25 (dt, 1H, J = 14.5, 8.1 Hz), 4.04 (dd, 2H, J = 7.6, 6.2Hz), 3.87 (q, 2H, J = 12.7, 10.5 Hz), 3.59 (d, 2H, J = 7.4 Hz), 3.48(ddd, 1H, J = 22.9, 5.4, 2.7 Hz), 3.39 (d, 1H, J = 13.1 Hz), 3.13 (q,2H, J = 7.4 Hz), J; Peak 2 (4S,5R)-1-{4-[(8- {3-[(ethane-sulfonyl)methyl] azetidin-1-yl} isoquinolin-3-yl) amino]pyrimidin-2-yl}-5-fluoro- 3,3-dimethyl- piperidin-4-ol or (4R,5S)-1-{4-[(8-{3-[(ethane- sulfonyl)methyl] azetidin-1-yl} isoquinolin-3-yl)amino]pyrimidin- 2-yl}-5-fluoro- 3,3-dimethyl- piperidin-4-ol

1.25 (t, 3H, J = 7.4 Hz), 1.04-0.74 (m, 6H) 28

529 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.05 (s, 1H), 8.65(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.47 (d,1H, J = 5.7 Hz), 6.42 (d, 1H, J = 8.0 Hz), 5.14 (d, 1H, J = 4.1 Hz),4.69 (d, 2H, J = 48.1 Hz), 4.39 (t, 3H, J = 7.6 Hz), 4.04-3.76 (m, 3H),3.56 (dd, 4H, J = 23.3, 7.4 Hz), 3.33- 3.21 (m, 2H), 3.02 (s, 3H),1.77-1.71 (m, 2H), 1.30 (dd, 6H, J = 6.8, 3.3 Hz) (3S,4R)-3-fluoro-1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl] piperidin-4-ol 29

529 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.88 (s, 1H), 9.05 (s, 1H), 8.65(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.47 (d,1H, J = 5.7 Hz), 6.42 (d, 1H, J = 8.1 Hz), 5.13 (d, 1H, J = 5.0 Hz),4.84-4.53 (m, 2H), 4.39 (t, 3H, J = 7.7 Hz), 4.02- 3.92 (m, 2H),3.88-3.76 (m, 1H), 3.68-3.45 (m, 4H, J = 23.1, 7.5 Hz), 3.30-3.23 (m,2H), 3.02 (s, 3H), 1.77- 1.71 (m, 2H), 1.30 (dd, 6H, J = 6.8, 3.3 Hz).(3R,4S)-3-fluoro- 1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]piperidin-4-ol 30

529 1H NMR (400 MHz, DMSO- d6) δ 9.85 (s, 1H), 9.02 (s, 1H), 8.38 (s,1H), 7.96 (d, J = 5.6 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.09 (d, J =8.1 Hz, 1H), 6.50 (d, J = 7.7 Hz, 1H), 6.39 (d, J = 5.6 Hz, 1H), 5.09(d, J = 5.4 Hz, 1H), 4.86- 4.62 (m, 2H), 4.22 (q, J = 6.4 Hz, 2H),3.93-3.78 (m, 2H), 3.72 (t, J = 7.1 Hz, 1H), 3.60-3.34 (m, 4H), 2.98 (s,3H), 2.88 (h, J = 7.3 Hz, 1H), 1.43 (d, J = 6.0 Hz, 3H), 0.94 (s, 6H).J; Peak 2 (4S,5R)-5-fluoro- 1-[4-({8-[(2R,3S)- 3-(methane-sulfonylmethyl)- 2-methylazetidin- 1-yl]isoquinolin- 3-yl}amino)pyrimidin-2-yl]- 3,3-dimethyl- piperidin-4-ol or (4R,5S)-5-fluoro-1-[4-({8- [(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]isoquinolin-3-

yl}amino) pyrimidin-2-yl]- 3,3-dimethyl- piperidin-4-ol 31

530 1H NMR (400 MHz, DMSO- d6) δ 10.06 (s, 1H), 9.01 (s, 1H), 8.39 (s,1H), 8.01 (d, J = 5.6 Hz, 1H), 7.88 (s, 1H), 6.49 (d, J = 5.7 Hz, 1H),5.00 (d, J = 6.4 Hz, 1H), 4.75- 4.62 (m, 2H), 4.56 (t, J = 8.4 Hz, 2H),4.21 (t, J = 7.4 Hz, 2H), 3.61-3.54 (m, 3H), 3.53-3.45 (m, 1H), 3.22-3.04 (m, 2H), 2.76 (q, J = 7.5 Hz, 2H), 1.77-1.67 (m, 2H), 1.35 (d, J =21.2 Hz, 3H), 1.26-1.20 (m, 5H). NN; Peak 1 (3S,4R)-1-[4-({5-ethyl-8-[3- (methanesulfonyl- methyl)azetidin-1- yl]-2,7-naph-thyridin-3-yl} amino)pyrimidin- 2-yl]-3-fluoro-3- methylpiperidin- 4-ol32

531 H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.02 (s, 1H), 8.86 (s,1H), 7.98 (d, 1H, J = 5.6 Hz), 7.00 (d, 1H, J = 8.3 Hz), 6.38 (dd, 2H, J= 7.0, 3.3 Hz), 5.01 (s, 1H), 4.87-4.56 (m, 2H), 4.30 (td, 2H, J = 7.6,2.3 Hz), 3.96-3.81 (m, 5H, J = 12.8 Hz), 3.59 (d, 2H, J = 7.4 Hz), 3.51(s, 1H), 3.32-3.08 (m, 3H), 3.02 (s, 3H), 1.88-1.62 (m, 2H), 1.38 (d,3H, J = 21.2 Hz) NN; Peak 1 (3S,4R)-3-fluoro- 1-[4-({8-[3-(methanesulfonyl- methyl)azetidin-1- yl]-5-methoxy- isoquinolin-3-yl}amino)pyrimidin- 2-yl]-3-methyl- piperidin-4-ol 33

533 1H NMR (400 MHz, DMSO- d6) δ 10.06 (s, 1H), 9.07 (s, 1H), 8.67 (s,1H), 7.99 (dd, J = 5.6, 1.1 Hz, 1H), 7.38- 7.27 (m, 1H), 6.43 (dd, J =8.5, 4.0 Hz, 1H), 6.38 (d, J = 5.7 Hz, 1H), 4.96 (d, J = 6.5 Hz, 1H),4.82-4.71 (m, 1H), 4.71-4.60 (m, 2H), 4.20 (q, J = 6.1 Hz, 1H), 3.65 (t,J = 7.1 Hz, 1H), 3.61-3.43 (m, 3H), 2.98 (s, 5H), 2.87 (q, J = 7.3 Hz,1H), 1.77-1.63 (m, 2H), 1.46-1.30 (m, 6H). NN; Peak 1(3S,4R)-3-fluoro-1- [4-({5-fluoro-8- [(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]isoquinolin-3- yl}amino)pyrimidin-2-yl]- 3-methyl- piperidin-4-ol 34

533 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.92 (s, 1H), 9.05 (s, 1H), 8.35(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.49 (t, 1H, J = 7.9 Hz), 7.04 (d,1H, J = 8.1 Hz), 6.48 (d, 1H, J = 5.7 Hz), 6.36 (d, 1H, J = 7.7 Hz),5.70 (d, 1H, J = 6.1 Hz), 4.64 (q, 1H, J = 11.4 Hz), 4.46 (t, 2H, J =7.8 Hz), 4.17 (d, 1H, J = 13.2 Hz), 4.04 (t, 2H, J = 6.9 Hz), 3.78-3.63(m, 1H), 3.63-3.59 (m, 1H), 3.55 (d, 2H, J = 22.2 Hz), 3.38-3.13 (m,1H), 3.02 (s, 3H), 1.03 (s, 3H), 0.91 (s, 3H) L; Peak 2(4R)-3,3-difluoro- 1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]isoquinolin- 3-yl}amino) pyrimidin-2-yl]- 5,5-dimethyl-piperidin-4-ol or (4S)-3,3-difluoro- 1-[4-({8-[3- (methanesulfonyl-methyl)azetidin- 1-yl]isoquinolin- 3-yl}amino) pyrimidin-2-yl]-5,5-dimethyl-

piperidin-4-ol 35

533 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.05 (s, 1H), 8.32(s, 1H), 8.01 (d, 1H, J = 5.6 Hz), 7.49 (t, 1H, J = 7.9 Hz), 7.12 (d,1H, J = 8.1 Hz), 6.51 (dd, 2H, J = 10.9, 6.7 Hz), 5.87 (s, 1H),4.90-4.65 (m, 2H), 4.36-4.12 (m, 3H), 3.96-3.83 (m, 2H), 3.81-3.67 (m,2H), 3.56 (t, 2H, J = 7.9 Hz), 3.00 (s, 3H), 2.90 (q, 1H, J = 7.2 Hz),1.48-1.41 (m, 6H) KK, Peak 2 (3R,4R,5R)-3,5- difluoro-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methyl- piperidin-4-ol or(3S,4S,5S)- 3,5-difluoro-1- [4-({8-[(2R,3S)- 3-(methane-sulfonylmethyl)- 2-methylazetidin- 1-yl]isoquinolin- 3-yl}amino)

pyrimidin-2-yl]- 3-methyl- piperidin-4-ol 36

533 1H NMR (400 MHz, DMSO- d6) δ 10.07 (s, 1H), 9.07 (s, 1H), 8.64 (s,1H), 8.01 (d, 1H, J = 5.6 Hz), 7.32 (dd, 1H, J = 10.3, 8.4 Hz), 6.44(dd, 2H, J = 11.9, 4.7 Hz), 4.92 (d, 1H, J = 49.2 Hz), 4.67 (q, 2H, J =9.3, 7.3 Hz), 4.45 (d, 1H, J = 12.9 Hz), 4.29-4.14 (m, 1H), 3.72-3.40(m, 4H), 3.34 (s, 3H), 3.32- 3.24 (m, 2H), 2.98 (s, 3H), 2.93-2.82 (m,1H), 1.83-1.64 (m, 2H), 1.40 (d, 3H, J = 6.0 Hz). 5-fluoro-N-{2-[(3S,4R)-3-fluoro- 4-methoxy- piperidin-1-yl] pyrimidin-4-yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]isoquinolin-3- amine 37

533 ¹H NMR (400 MHz, DMSO- d₆) δ 10.11 (s, 1H), 9.09 (s, 1H), 8.65 (s,1H), 8.03 (d, J = 5.6 Hz, 1H), 7.33 (dd, J = 10.3, 8.4 Hz, 1H), 6.52-6.37 (m, 2H), 4.93 (d, J = 49.3 Hz, 1H), 4.69 (t, J = 7.6 Hz, 2H), 4.44(d, J = 13.0 Hz, 1H), 4.21 (t, J = 6.2 Hz, 1H), 3.78-3.39 (m, 4H), 3.36(s, 3H), 3.30-3.26 (m, 2H), 3.00 (s, 3H), 2.88 (q, J = 7.3 Hz, 1H),1.94- 1.63 (m, 2H), 1.42 (d, J = 6.0 Hz, 3H) 5-fluoro-N-{2-[(3R,4S)-3-fluoro- 4-methoxy- piperidin-1-yl] pyrimidin-4-yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]isoquinolin-3- amine 38

537 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.87 (s, 1H), 9.05 (s, 1H), 8.65(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.46 (d,1H, J = 5.7 Hz), 6.42 (d, 1H, J = 8.1 Hz), 4.46 (t, 2H, J = 7.7 Hz),4.39 (t, 2H, J = 7.6 Hz), 3.97 (t, 2H, J = 6.9 Hz), 3.91-3.72 (m, 5H),3.59 (d, 2H, J = 7.4 Hz), 3.48 (p, 1H, J = 6.7 Hz), 3.28 (dd, 2H, J =14.1, 6.8 Hz), 2.43 (t, 2H, J = 7.7 Hz), 1.84 (q, 5H, J = 6.5, 5.9 Hz),1.32 (d, 6H, J = 6.8 Hz) 8-[3-(methane- sulfonylmethyl)azetidin-1-yl]-N- (2-{1-oxa-7- azaspiro[3.5] nonan-7-yl}pyrimidin-4-yl)- 5-(propan-2-yl) isoquinolin-3- amine 39

537 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.85 (s, 1H), 9.04 (s, 1H), 8.74(s, 1H), 7.97 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.47-6.33(m, 2H), 4.75 (d, 1H, J = 2.5 Hz), 4.57-4.27 (m, 4H), 3.95 (dd, 3H, J =14.3, 7.4 Hz), 3.59 (d, 2H, J = 7.4 Hz), 3.55-3.42 (m, 1H), 3.08-2.94(m, 5H), 2.25-2.05 (m, 2H), 1.93-1.73 (m, 2H), 1.40 (d, 2H, J = 7.5 Hz),1.30 (d, 6H, J = 6.7 Hz) Rac (1R,5S,8S)- 3-[4-({8-[3- (methanesulfonyl-methyl)azetidin- 1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]-3- azabicyclo[3.2.1] octan-8-ol 40

537 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.90 (s, 1H), 9.06 (s, 1H), 8.76(s, 1H), 7.97 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 4.66 (t, 1H, J = 7.5 Hz), 4.28-4.23 (m, 1H), 4.19 (t,3H, J = 6.4 Hz), 3.93-3.59 (m, 3H), 3.59- 3.36 (m, 5H), 3.00 (s, 3H),2.89 (q, 1H, J = 7.3 Hz), 2.64 (dt, 1H, J = 11.4, 5.9 Hz), 2.13-2.03 (m,1H), 1.91 (p, 1H, J = 10.0 Hz), 1.43 (d, 3H, J = 6.0 Hz), 1.29 (d, 6H, J= 6.6 Hz) F; Peak 2 N-{2-[(3aR,6aS)- hexahydro-1H- furo[3,4-b]pyrrol-1-yl]pyrimidin-4- yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine or N-{2-[(3aS,6aR)- hexahydro-1H- furo[3,4-b]pyrrol- 1-yl]pyrimidin-4-yl}-8-[(2R,3S)-3-

(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- amine 41

537 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.05 (s, 1H), 8.70(s, 1H), 8.01 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.45 (d, 1H, J = 5.5 Hz), 5.53 (s, 1H), 4.74-4.61 (m,1H), 4.54 (s, 2H), 4.23-4.17 (m, 1H), 4.01-3.91 (m, 1H), 3.90-3.84 (m,1H), 3.67-3.44 (m, 4H), 3.00 (s, 3H), 2.93-2.87 (m, 1H), 1.91-1.76 (m,2H), 1.74-1.68 (m, 2H), 1.42 (d, 3H, J = 5.8 Hz), 1.33-1.24 (m, 6H) M;Peak 2 N-(2-((1S,5R)-6- oxa-2-azabicyclo [3.2.1]octan-2- yl)pyrimidin-4-yl)-5-isopropyl- 8-((2S,3R)-2- methyl-3- ((methylsulfonyl)methyl)azetidin- 1-yl)isoquinolin- 3-amine or N-(2- ((1R,5S)-6-oxa-2-azabicyclo [3.2.1]octan-2-yl) pyrimidin-4-yl)- 5-isopropyl-8-((2S,3R)-2-

methyl-3- ((methylsulfonyl) methyl)azetidin- 1-yl)isoquinolin- 3-amine42

538 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.45 (s, 1H), 9.09 (s, 1H), 8.68(s, 1H), 8.46 (s, 1H), 7.45 (d, 1H, J = 8.0 Hz), 6.45 (d, 1H, J = 8.0Hz), 4.42 (dt, 4H, J = 18.4, 7.6 Hz), 3.98 (q, 2H, J = 6.9, 6.1 Hz),3.89-3.80 (m, 4H), 3.57 (d, 2H, J = 7.4 Hz), 3.50-3.40 (m, 1H), 3.00 (s,3H), 2.42 (t, 2H, J = 7.7 Hz), 1.91-1.81 (m, 4H), 1.30 (d, 6H, J = 6.7Hz) 8-[3-(methane- sulfonylmethyl) azetidin-1-yl]- N-(3-{1-oxa-7-azaspiro[3.5] nonan-7-yl}- 1,2,4-triazin-5- yl)-5-(propan- 2-yl)iso-quinolin-3- amine 43

538 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.14 (s, 1H), 9.13 (s, 1H), 8.90(s, 1H), 8.01 (d, 1H, J = 5.7 Hz), 7.73 (s, 1H), 6.51 (s, 1H), 4.74 (t,1H, J = 7.5 Hz), 4.39-4.13 (m, 4H), 3.90-3.74 (m, 1H), 3.75 (s, 3H),3.54 (dt, 2H, J = 10.1, 5.0 Hz), 3.51-3.42 (m, 2H), 3.01 (s, 3H), 2.93(q, 1H, J = 7.2 Hz), 2.74- 2.60 (m, 1H), 2.12-2.05 (m, 1H), 1.99-1.86(m, 1H), 1.48 (d, 3H, J = 6.0 Hz), 1.30 (dd, 6H, J = 6.7, 3.4 Hz) F;Peak 2 N-{2-[(3aR,6aS)- hexahydro-1H- furo[3,4-b]pyrrol-1-yl]pyrimidin-4- yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)-2,6-naph- thyridin-3-amine orN-{2- [(3aS,6aR)- hexahydro-1H- furo[3,4-b]pyrrol- 1-yl]pyrimidin-4-

yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)-2,6-naph- thyridin-3-amine 44

539 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.80 (s, 1H), 9.04 (s, 1H), 8.69(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.41 (d,1H, J = 8.0 Hz), 6.38 (d, 1H, J = 5.6 Hz), 5.10-5.04 (m, 1H), 4.66-4.55(m, 1H), 4.39 (t, 2H, J = 7.6 Hz), 4.31 (s, 1H), 3.97 (t, 2H, J = 6.9Hz), 3.59 (d, 2H, J = 7.4 Hz), 3.49 (q, 1H, J = 6.8 Hz), 3.30-3.20 (m,1H), 3.02 (s, 3H), 1.68-1.58 (m, 3H), 1.55-1.41 (m, 1H), 1.39-1.25 (m,9H), 1.16 (s, 3H) H; Peak 1 (2R,4R)-1-[4-({8- [3-(methane-sulfonylmethyl) azetidin-1-yl]-5- (propan-2-yl) isoquinolin-3-yl}amino)pyrimidin- 2-yl]-2,4- dimethylpiperidin- 4-ol or (2S,4S)-1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino)

pyrimidin-2-yl]- 2,4-dimethyl- piperidin-4-ol 45

539 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.80 (s, 1H), 9.04 (s, 1H), 8.69(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.46-6.34(m, 2H), 5.08-5.02 (m, 1H), 4.60 (d, 1H, J = 12.9 Hz), 4.39 (t, 2H, J =7.7 Hz), 4.31 (s, 1H), 3.97 (t, 2H, J = 6.9 Hz), 3.59 (d, 2H, J = 7.4Hz), 3.55-3.45 (m, 1H), 3.32-3.26 (m, 1H), 3.02 (s, 3H), 1.68- 1.58 (m,3H), 1.55-1.40 (m, 1H), 1.39-1.25 (m, 9H), 1.16 (s, 3H) H; Peak 2(2S,4S)-1-[4-({8- [3-(methane- sulfonylmethyl) azetidin-1-yl]-5-(propan-2-yl) isoquinolin-3-yl} amino)pyrimidin- 2-yl]-2,4-dimethylpiperidin- 4-ol or (2R,4R)-1- [4-({8-[3- (methanesulfonyl-methyl)azetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)

pyrimidin-2-yl]- 2,4-dimethyl- piperidin-4-ol 46

539 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.84 (s, 1H), 9.04 (s, 1H), 8.70(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.55 (d,1H, J = 8.0 Hz), 6.39 (d, 1H, J = 5.6 Hz), 4.65 (t, 1H, J = 7.5 Hz),4.39 (s, 1H), 4.27 (s, 1H), 4.20 (td, 2H, J = 12.6, 12.2, 5.3 Hz), 3.63(t, 1H, J = 7.2 Hz), 3.51 (ddd, 4H, J = 16.0, 8.2, 4.8 Hz), 3.45 (d, 1H,J = 4.4 Hz), 2.99 (s, 3H), 2.88 (q, 1H, J = 7.3 Hz), 1.53 (td, 4H, J =13.4, 12.7, 6.4 Hz), 1.42 (d, 3H, J = 6.0 Hz), 1.29 (d, 6H, J = 6.7 Hz),1.18 (s, 3H) K; Peak 1 1-[4-({8-[(2R,3S)- 3-(methane- sulfonylmethyl)-2-methylazetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino)pyrimidin-2-yl]- 4-methyl- piperidin-4-ol 47

539 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.85 (s, 1H), 9.05 (s, 1H), 8.71(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 7.9 Hz), 6.56 (d,1H, J = 8.0 Hz), 6.37 (d, 1H, J = 5.6 Hz), 5.01 (s, 1H), 4.72-4.51 (m,3H), 4.25-4.14 (m, 1H), 4.05 (s, 1H), 3.72- 3.42 (m, 4H), 3.00 (s, 3H),2.90 (t, 1H, J = 7.3 Hz), 1.83-1.67 (m, 4H), 1.43 (d, 3H, J = 5.9 Hz),1.38-1.17 (m, 9H) E; Peak 1 (2S,4S)-1-[4-({8- [(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 2-methyl- piperidin-4-ol or(2R,4R)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1-

yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 2-methyl-piperidin-4-ol 48

539 1H-NMR (300 MHz, CDCl3) δ ppm 9.09 (s, 1H), 8.68 (s, 1H), 8.08 (d,1H, J = 5.6 Hz), 7.60 (s, 1H), 7.41 (d, 1H, J = 7.9 Hz), 6.54 (d, 1H, J= 8.0 Hz), 6.09 (d, 1H, J = 5.6 Hz), 5.15 (t, 1H, J = 6.8 Hz), 4.70 (q,2H, J = 7.5, 6.5 Hz), 4.36-4.19 (m, 2H), 3.74-3.23 (m, 5H), 3.07 (p, 1H,J = 7.2 Hz), 2.97 (s, 3H), 2.14-1.65 (m, 5H), 1.51 (dd, 6H, J = 8.9, 6.5Hz), 1.38 (dd, 6H, J = 6.8, 2.4 Hz) E; Peak 2 (2R,4R)-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 2-methyl-piperidin-4-ol or (2S,4S)-1-[4-({8- [(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1-

yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 2-methyl-piperidin-4-ol 49

539 1H-NMR (300 MHz, CDCl3) δ ppm 9.10 (s, 1H), 8.63 (s, 1H), 8.10 (d,1H, J = 5.7 Hz), 7.43 (d, 1H, J = 7.9 Hz), 6.56 (d, 1H, J = 8.0 Hz),6.14 (s, 1H), 5.37 (d, 1H, J = 7.0 Hz), 4.91 (d, 1H, J = 13.3 Hz), 4.70(t, 1H, J = 7.6 Hz), 4.33- 4.23 (m, 1H), 4.20-4.14 (m, 1H), 3.63 (dt,2H, J = 26.5, 7.0 Hz), 3.37 (t, 2H, J = 7.2 Hz), 3.21-3.01 (m, 2H), 2.98(s, 3H), 2.13 (d, 1H, J = 12.5 Hz), 2.04 (d, 1H, J = 12.1 Hz), 1.73 (dt,2H, J = 11.9, 5.9 Hz), 1.58-1.50 (m, 4H), 1.39 (dd, L; Peak 2(2R,4S)-1-[4-({8- [(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 2-methyl- piperidin-4-ol or (2S,4R)-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-

6H, J = 6.8, 2.3 Hz), 1.31 (d, 3H, J = 7.0 Hz) yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 2-methyl- piperidin-4-ol 50

540 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.10 (s, 1H), 9.04 (s, 1H), 8.56(s, 1H), 8.05 (d, 1H, J = 5.6 Hz), 8.01 (s, 1H), 6.48 (d, 1H, J = 5.6Hz), 4.86 (t, 1H, J = 7.9 Hz), 4.55 (t, 1H, J = 6.2 Hz), 4.27 (d, 2H, J= 13.5 Hz), 3.98 (t, 1H, J = 7.3 Hz), 3.58-3.35 (m, 5H), 3.31 (s, 3H),3.30- 3.24 (m, 1H), 2.99 (s, 3H), 2.94-2.85 (m, 1H), 1.95- 1.89 (m, 2H),1.58-1.40 (m, 5H), 1.32 (dd, 6H, J = 6.8, 4.1 Hz) 8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-N-[2-(4-methoxypiperidin- 1-yl)pyrimidin-4- yl]-5-(propan-2- yl)-2,7-naph-thyridin-3-amine 51

541 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.86 (s, 1H), 9.05 (s, 1H), 8.69(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.24 (d, 1H, J = 7.8 Hz), 6.50 (d,1H, J = 5.7 Hz), 6.31 (d, 1H, J = 7.9 Hz), 4.99 (d, 1H, J = 6.4 Hz),4.72 (dt, 2H, J = 20.8, 10.7 Hz), 4.40 (t, 2H, J = 7.6 Hz), 3.97 (t, 2H,J = 6.9 Hz), 3.63-3.57 (m, 1H), 3.61-3.43 (m, 2H), 3.22-3.05 (m, 1H),3.02 (s, 3H), 1.69- 1.63 (m, 2H), 1.32 (d, 4H, J = 21.2 Hz), 1.02-0.92(m, 2H), 0.65 (d, 2H, J = 6.1 Hz) NN; Peak 1 (3S,4R)-1-[4-({5-cyclopropyl-8-[3- (methanesulfonyl- methyl)azetidin-1- yl]isoquinolin-3-yl}amino) pyrimidin-2-yl]- 3-fluoro-3- methylpiperidin- 4-ol 52

541 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.83 (s, 1H), 9.04 (s, 1H), 8.67(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.42 (t,2H, J = 6.8 Hz), 4.62 (d, 1H, J = 5.0 Hz), 4.39 (t, 2H, J = 7.6 Hz),3.96 (t, 4H, J = 6.9 Hz), 3.79 (s, 1H), 3.71 (d, 1H, J = 12.8 Hz),3.64-3.50 (m, 4H), 3.48 (t, 1H, J = 8.6 Hz), 3.37 (s, 3H), 3.02 (s, 3H),1.88 (s, 1H), 1.63 (s, 1H), 1.30 (d, 6H, J = 6.7 Hz) (3S,4R)-1-[4-({8-[3-(methane- sulfonylmethyl) azetidin-1-yl]-5- (propan-2-yl)isoquinolin-3-yl} amino)pyrimidin- 2-yl]-4-methoxy- piperidin-3-ol or(3R,4S)-1-(4- ((5-isopropyl-8- (3-((methyl- sulfonyl)methyl)azetidin-1-yl) isoquinolin-3- yl)amino)

pyrimidin-2-yl)- 4-methoxy- piperidin-3-ol 53

541 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.85 (s, 1H), 9.05 (s, 1H), 8.64(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.47 (d,1H, J = 5.7 Hz), 6.41 (d, 1H, J = 8.1 Hz), 5.08 (d, 1H, J = 4.8 Hz),4.39 (t, 4H, J = 7.8 Hz), 3.96 (t, 2H, J = 6.9 Hz), 3.59 (d, 2H, J = 7.4Hz), 3.56-3.46 (m, 1H), 3.44-3.36 (m, 5H), 3.31-3.08 (m, 4H), 3.02 (s,3H), 2.07-2.01 (m, 1H), 1.35-1.21 (m, 7H) C; Peak 1 (3S,4S)-1-[4-({8-[3-(methane- sulfonylmethyl) azetidin-1-yl]-5- (propan-2-yl)isoquinolin-3-yl} amino)pyrimidin- 2-yl]-4-methoxy- piperidin-3-ol or(3R,4R)-1-[4- ({8-[3-(methane- sulfonylmethyl) azetidin-1-yl]-5-(propan-2-yl) isoquinolin-3-yl} amino)pyrimidin-

2-yl]-4-methoxy- piperidin-3-ol 54

541 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.85 (s, 1H), 9.05 (s, 1H), 8.64(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.47 (d,1H, J = 5.7 Hz), 6.41 (d, 1H, J = 8.1 Hz), 5.08 (d, 1H, J = 4.8 Hz),4.39 (t, 4H, J = 7.9 Hz), 3.96 (t, 2H, J = 6.9 Hz), 3.59 (d, 2H, J = 7.4Hz), 3.50 (dt, 1H, J = 14.2, 7.1 Hz), 3.39 (s, 3H), 3.32-3.21 (m, 1H),3.31 (s, 3H), 3.21-3.01 (m, 1H), 3.02 (s, 3H), 2.07- 2.01 (m, 1H),1.42-1.20 (m, 7H) C; Peak 2 (3R,4R)-1-[4-({8- [3-(methane-sulfonylmethyl) azetidin-1-yl]-5- (propan-2-yl) isoquinolin-3-yl}amino)pyrimidin- 2-yl]-4-methoxy- piperidin-3-ol or (3S,4S)-1-[4-({8-[3-(methane- sulfonylmethyl) azetidin-1-yl]-5- (propan-2-yl)isoquinolin-3-yl} amino)pyrimidin-

2-yl]-4-methoxy- piperidin-3-ol 55

543 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.86 (s, 1H), 9.06 (s, 1H), 8.61(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.48 (d,1H, J = 5.7 Hz), 6.41 (d, 1H, J = 8.1 Hz), 5.03 (d, 1H, J = 6.4 Hz),4.92-4.58 (m, 2H), 4.39 (t, 2H, J = 7.8 Hz), 3.97 (t, 2H, J = 6.8 Hz),3.67-3.45 (m, 4H), 3.20-3.07 (m, 3H), 3.02 (s, 3H), 1.74 (s, 2H),1.51-1.15 (m, 9H) NN; Peak 1 (3S,4R)-3-fluoro- 1-[4-({8-[3-(methanesulfonyl- methyl)azetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 3-methyl- piperidin-4-ol 56

543 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.91 (s, 1H), 9.05 (s, 1H), 8.65(s, 1H), 8.01 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.49 (d,1H, J = 5.7 Hz), 6.42 (d, 1H, J = 8.0 Hz), 4.85 (s, 1H), 4.55-4.23 (m,4H), 4.20 (d, 1H, J = 13.1 Hz), 3.97 (t, 2H, J = 6.9 Hz), 3.69-3.55 (m,3H), 3.56-3.41 (m, 2H), 3.32-3.22 (m, 1H), 3.02 (s, 3H), 1.82-1.50 (m,2H), 1.38-1.17 (m, 9H) F; Peak 1 (3S,4R)-3-fluoro- 1-[4-({8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 4-methyl- piperidin-4-ol 57

543 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.06 (s, 1H), 8.64(s, 1H), 8.01 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.49 (d,1H, J = 5.6 Hz), 6.42 (d, 1H, J = 8.0 Hz), 4.86 (s, 1H), 4.40 (q, 2H, J= 7.7, 6.5 Hz), 4.29 (dd, 1H, J = 9.0, 4.3 Hz), 4.19 (d, 1H, J = 13.0Hz), 3.97 (t, 2H, J = 6.9 Hz), 3.63 (s, 1H), 3.59 (d, 2H, J = 7.4 Hz),3.55-3.45 (m, 2H), 3.33-3.23 (m, 1H), 3.02 (s, 3H), 1.72 (d, 1H, J =12.6 Hz), 1.57 (t, 1H, J = 10.3 Hz), 1.33-1.22 (m, 9H) F; Peak 2(3R,4S)-3-fluoro- 1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methyl-piperidin-4-ol 58

543 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.87 (s, 1H), 9.04 (d, 1H, J = 0.8Hz), 8.82 (s, 1H), 7.99 (d, 1H, J = 5.7 Hz), 7.41 (d, 1H, J = 8.0 Hz),6.46 (d, 1H, J = 5.7 Hz), 6.40 (d, 1H, J = 8.1 Hz), 5.20 (s, 1H), 4.38(t, 2H, J = 7.7 Hz), 3.96 (t, 2H, J = 6.9 Hz), 3.93-3.81 (m, 2H),3.80-3.64 (m, 2H), 3.59 (d, 2H, J = 7.4 Hz), 3.55-3.45 (m, 1H),3.30-3.22 (m, 1H), 3.01 (s, 3H), 2.35-2.08 (m, 2H), 1.29 (dd, 6H, J =6.7, 1.9 Hz), 1.21 (d, 3H, J = 6.4 Hz) F; Peak 1 (1R)-1-[(3R)-3-fluoro-1-[4-({8- [3-(methane- sulfonylmethyl) azetidin-1-yl]-5-(propan-2-yl) isoquinolin-3-yl} amino)pyrimidin- 2-yl]pyrrolidin-3-yl]ethan-1-ol or (1S)-1-[(3S)- 3-fluoro-1-[4- ({8-[3-(methane-sulfonylmethyl) azetidin-1-yl]-5- (propan-2-yl)

isoquinolin-3-yl} amino)pyrimidin- 2-yl]pyrrolidin-3- yl]ethan-1-ol 59

543 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.85 (s, 1H), 9.04 (s, 1H), 8.81(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.40 (d, 1H, J = 8.0 Hz), 6.47 (d,1H, J = 5.6 Hz), 6.40 (d, 1H, J = 8.0 Hz), 5.16 (d, 1H, J = 5.9 Hz),4.38 (t, 2H, J = 7.6 Hz), 3.96 (t, 2H, J = 6.9 Hz), 3.92-3.65 (m, 4H),3.58 (d, 2H, J = 7.4 Hz), 3.54-3.41 (m, 1H), 3.31-3.17 (m, 1H), 3.01 (s,3H), 2.35-2.04 (m, 2H), 1.29 (d, 6H, J = 6.7 Hz), 1.24-1.18 (m, 3H) F;Peak 2 (1R)-1-[(3S)-3- fluoro-1-[4-({8- [3-(methane- sulfonylmethyl)azetidin-1-yl]-5- (propan-2-yl) isoquinolin-3-yl} amino)pyrimidin-2-yl]pyrrolidin-3- yl]ethan-1-ol or (1S)-1-[(3R)-3- fluoro-1-[4-({8-[3-(methane- sulfonylmethyl) azetidin-1-yl]-5- (propan-2-yl)

isoquinolin-3-yl} amino)pyrimidin- 2-yl]pyrrolidin-3- yl]ethan-1-ol 60

543 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.90 (s, 1H), 9.05 (s, 1H), 8.46(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.57-7.32 (m, 1H), 6.44 (d, 1H, J =5.7 Hz), 6.33 (d, 1H, J = 7.8 Hz), 5.13 (d, 1H, J = 5.4 Hz), 4.96-4.60(m, 1H), 4.39 (t, 2H, J = 7.6 Hz), 4.24 (dt, 1H, J = 14.5, 8.0 Hz),4.09-3.87 (m, 3H), 3.81 (d, 1H, J = 12.9 Hz), 3.58 (d, 2H, J = 7.4 Hz),3.53-3.39 (m, 2H), 3.33-3.25 (m, 1H), 3.13 (q, 2H, J = 7.4 Hz), 2.51 (s,3H), 1.25 (t, 3H, J = 7.4 Hz), 1.01-0.79 (m, 6H) J; Peak 2(4S,5R)-1-{4-[(8- {3-[(ethane- sulfonyl)methyl] azetidin-1-yl}-5-methylisoquinolin- 3-yl)amino] pyrimidin-2-yl}-5- fluoro-3,3-dimethylpiperidin- 4-ol or (4R,5S)-1- {4-[(8-{3- [(ethanesulfonyl)methyl]azetidin-1- yl}-5-methyl- isoquinolin-3-yl) amino]pyrimidin-2-yl}-5-fluoro- 3,3-dimethyl-

piperidin-4-ol 61

543 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.88 (s, 1H), 9.05 (s, 1H), 8.63(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 7.9 Hz), 6.47 (d,1H, J = 5.6 Hz), 6.42 (d, 1H, J = 8.1 Hz), 5.34 (d, 1H, J = 4.3 Hz),4.39 (t, 2H, J = 7.6 Hz), 4.02-3.88 (m, 6H), 3.79-3.73 (m, 1H), 3.59 (d,2H, J = 7.4 Hz), 3.51 (t, 1H, J = 7.0 Hz), 3.02 (s, 3H), 1.93-1.87 (m,1H), 1.60-1.52 (m, 1H), 1.38-1.24 (m, 9H) D; Peak 2 (3S,4S)-3-fluoro-1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methyl- piperidin-4-ol or(3R,4R)-3-fluoro- 1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan-2- yl)isoquinolin-3-

yl}amino) pyrimidin-2-yl]- 3-methyl- piperidin-4-ol 62

543 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.04 (s, 1H), 8.64(s, 1H), 7.98 (d, 1H, J = 5.7 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.55 (d,1H, J = 8.1 Hz), 6.43 (d, 1H, J = 5.7 Hz), 5.11 (d, 1H, J = 5.0 Hz),4.79-4.53 (m, 3H), 4.36 (d, 1H, J = 13.4 Hz), 4.17 (q, 1H, J = 6.2 Hz),3.97-3.76 (m, 1H), 3.65-3.42 (m, 5H), 3.39-3.34 (m, 1H), 2.98 (s, 3H),2.87 (q, 1H, J = 7.2 Hz), 1.75-1.67 (m, 2H), 1.41 (d, 3H, J = 6.0 Hz),1.29 (dd, 6H, J = 6.7, 1.9 Hz) (3S,4R)-3-fluoro- 1-(4-((5- isopropyl-8-((2R,3S)-2- methyl-3- ((methylsulfonyl) methyl)azetidin-1-yl)isoquinolin-3- yl)amino) pyrimidin-2-yl) piperidin-4-ol 63

543 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.88 (s, 1H), 9.05 (s, 1H), 8.61(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.48 (d,1H, J = 5.6 Hz), 6.41 (d, 1H, J = 8.0 Hz), 4.94 (d, 1H, J = 48.4 Hz),4.73 (m, 1H), 4.48 (d, 1H, J = 12.8 Hz), 4.39 (t, 2H, J = 7.6 Hz), 3.96(t, 2H, J = 6.9 Hz), 3.59 (d, 2H, J = 7.4 Hz), 3.65-3.40 (m, 3H), 3.37(s, 3H), 3.40- 3.15 (m, 2H), 3.01 (s, 3H), 1.78 (d, 2H, J = 25.6 Hz),1.30 (dd, 6H, J = 6.8, 4.2 Hz) N-{2-[(3R,4S)- 3-fluoro-4- methoxy-piperidin-1-yl] pyrimidin-4-yl}- 8-[3-(methane- sulfonylmethyl)azetidin-1-yl]- 5-(propan-2- yl)isoquinolin- 3-amine 64

543 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.90 (s, 1H), 9.05 (s, 1H), 8.62(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 7.9 Hz), 6.48 (d,1H, J = 5.7 Hz), 6.41 (d, 1H, J = 8.1 Hz), 4.94 (d, 1H, J = 49.8 Hz),4.74 (s, 1H), 4.49 (d, 1H, J = 13.4 Hz), 4.39 (t, 2H, J = 7.6 Hz), 3.96(t, 2H, J = 6.9 Hz), 3.70-3.42 (m, 6H), 3.37 (s, 3H), 3.31- 3.20 (m,1H), 3.01 (s, 3H), 1.84-1.68 (m, 2H), 1.30 (dd, 6H, J = 6.8, 3.2 Hz)N-{2-[(3S,4R)- 3-fluoro-4- methoxy- piperidin-1-yl] pyrimidin-4-yl}-8-[3-(methane- sulfonylmethyl) azetidin-1-yl]-5- (propan-2-yl)isoquinolin-3- amine 65

543 1H NMR (400 MHz, DMSO- d6) δ 9.86 (s, 1H), 9.03 (s, 1H), 8.51 (s,1H), 7.96 (d, J = 5.7 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 6.50 (d, J =7.9 Hz, 1H), 6.43 (d, J = 5.7 Hz, 1H), 4.99 (d, J = 6.4 Hz, 1H),4.79-4.58 (m, 3H), 4.17 (p, J = 6.1 Hz, 1H), 3.65-3.44 (m, 4H),3.21-3.03 (m, 2H), 2.98 (s, 3H), 2.94-2.81 (m, 3H), 1.77-1.67 (m, 2H),1.42-1.30 (m, 6H), 1.26 (t, J = 7.4 Hz, 3H). NN; Peak 1 (3S,4R)-1-[4-({5-ethyl-8- [(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-fluoro-3-methylpiperidin- 4-ol 66

543 1H NMR (400 MHz, DMSO- d6) δ 9.90 (s, 1H), 9.07 (s, 1H), 8.43 (s,1H), 8.01 (d, J = 5.6 Hz, 1H), 7.51 (t, 1H, J = 7.9 Hz), 7.13 (d, 1H, J= 8.1 Hz), 6.54 (d, 1H, J = 7.7 Hz), 6.44 (d, 1H, J = 5.6 Hz), 5.14 (d,1H, J = 5.4 Hz), 4.92- 4.64 (m, 2H), 4.35-4.19 (m, 2H), 3.88 (d, 2H, J =13.5 Hz), 3.76 (t, 1H, J = 7.2 Hz), 3.65-3.37 (m, 4H), 3.13 (q, 2H, J =7.4 Hz), 2.92 (q, 1H, J = 7.1 Hz), 1.47 (d, 3H, J = 6.0 Hz), 1.26 (t,3H, J = 7.4 Hz), 1.05-0.95 (m, 6H). J; Peak 2 (4S,5R)-1-[4-({8-[(2R,3S)-3- [(ethanesulfonyl) methyl]-2- methylazetidin-1-yl]isoquinolin- 3-yl}amino) pyrimidin-2-yl]- 5-fluoro-3,3- dimethyl-piperidin-4-ol or (4R,5S)-1-[4- ({8-[(2R,3S)-3- [(ethanesulfonyl)methyl]-2- methylazetidin- 1-yl]isoquinolin- 3-yl}amino)

pyrimidin-2-yl]- 5-fluoro-3,3- dimethyl- piperidin-4-ol 67

544 1H NMR (400 Hz, DMSO- d6) δ 10.08 (s, 1H), 9.05 (s, 1H), 8.50 (s,1H), 8.06 (d, J = 5.6 Hz, 1H), 8.01 (s, 1H), 6.54 (d, J = 5.7 Hz, 1H),5.04 (d, J = 6.4 Hz, 1H), 4.80- 4.64 (m, 2H), 4.59 (t, J = 8.4 Hz, 2H),4.25 (ddd, J = 8.5, 6.2, 1.8 Hz, 2H), 3.67-3.49 (m, 3H), 3.25-3.10 (m,2H), 3.03 (s, 3H), 1.77 (d, J = 7.6 Hz, 2H), 1.46-1.24 (m, 9H). NN; Peak1 (3S,4R)-3-fluoro- 1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)-2,7- naphthyridin-3- yl}amino) pyrimidin-2-yl]-3-methyl- piperidin-4-ol 70

544 1H NMR (400 MHz, 6d- DMSO) δ ppm 10.12 (s, 1H), 9.13 (s, 1H), 8.73(s, 1H), 8.03 (d, 1H, J = 5.6 Hz), 7.60 (s, 1H), 6.46 (d, 1H, J = 5.7Hz), 5.06 (d, 1H, J = 6.4 Hz), 4.81-4.71 (m, 1H), 4.67 (s, 1H), 4.49 (t,2H, J = 7.8 Hz), 4.08 (t, 2H, J = 13.3 Hz), 3.75-3.66 (m, 1H), 3.61 (d,2H, J = 7.4 Hz), 3.58-3.51 (m, 1H), 3.32 (m, 1H), 3.16 (m, 2H), 3.03 (s,3H), 1.75 (s, 2H), 1.40-1.28 (m, 9H) NN; Peak 1 (3S,4R)-3-fluoro-1-[4-({8-[3- (methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan-2-yl)-2,6- naphthyridin-3- yl}amino) pyrimidin-2-yl]- 3-methyl-piperidin-4-ol 71

544 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.11 (s, 1H), 9.02 (s, 1H), 8.50(s, 1H), 8.04 (d, 1H, J = 5.6 Hz), 7.98 (s, 1H), 6.52 (d, 1H, J = 5.7Hz), 4.96 (d, 1H), 4.77-4.66 (m, 1H), 4.56 (t, 2H, J = 8.4 Hz),4.50-4.42 (m, 1H), 4.22 (dd, 2H, J = 8.6, 6.2 Hz), 3.67-3.56 (m, 3H),3.47 (dd, 1H, J = 31.9, 14.0 Hz), 3.37 (s, 3H), 3.33-3.26 (m, 3H), 3.01(s, 3H), 1.87-1.69 (m, 2H), 1.31 (dd, 6H, J = 6.8, 4.3 Hz)N-{2-[(3R,4S)- 3-fluoro-4- methoxypiperidin- 1-yl]pyrimidin-4- yl}-8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan- 2-yl)-2,7-naphthyridin-3- amine 72

544 1H-NMR (400 MHz. 6d- DMSO) δ ppm 10.11 (s, 1H), 9.02 (s, 1H), 8.50(s, 1H), 8.04 (d, 1H, J = 5.6 Hz), 7.98 (s, 1H), 6.52 (d, 1H, J = 5.7Hz), 4.96 (d, 1H), 4.71 (ddd, 1H, J = 14.1, 9.4, 5.2 Hz), 4.56 (t, 2H, J= 8.4 Hz), 4.47 (d, 1H, J = 13.3 Hz), 4.22 (dd, 2H, J = 8.6, 6.2 Hz),3.66-3.54 (m, 3H), 3.47 (dd, 1H, J = 31.9, 14.0 Hz), 3.37 (s, 3H),3.31-3.23 (m, 3H), 3.01 (s, 3H), 1.89-1.68 (m, 2H), 1.31 (dd, 6H, J =6.8, 4.3 Hz) N-{2-[(3S,4R)- 3-fluoro-4- methoxypiperidin-1-yl]pyrimidin-4- yl}-8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)-2,7- naphthyridin-3- amine 73

544 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.15 (s, 1H), 9.13 (s, 1H), 8.74(s, 1H), 8.04 (d, 1H, J = 5.6 Hz), 7.60 (s, 1H), 6.48 (d, 1H, J = 5.7Hz), 4.96 (d, 1H, J = 50.1 Hz), 4.75 (s, 1H), 4.49 (t, 3H, J = 7.7 Hz),4.07 (t, 2H, J = 6.9 Hz), 3.82-3.42 (m, 5H), 3.38 (s, 3H), 3.35-3.23 (m,2H), 3.03 (s, 3H), 1.86- 1.73 (m, 2H), 1.31 (dd, 6H, J = 6.7, 3.5 Hz)N-{2-[(3R,4S)- 3-fluoro-4- methoxypiperidin- 1-yl]pyrimidin-4- yl}-8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan- 2-yl)-2,6-naphthyridin-3- amine 74

544 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.15 (s, 1H), 9.13 (s, 1H), 8.74(s, 1H), 8.04 (d, 1H, J = 5.7 Hz), 7.60 (s, 1H), 6.48 (d, 1H, J = 5.7Hz), 4.96 (d, 1H, J = 49.4 Hz), 4.76-4.70 (m, 1H), 4.49 (t, 2H, J = 7.7Hz), 4.08 (t, 2H, J = 6.9 Hz), 3.78-3.40 (m, 6H), 3.38 (s, 3H), 3.33-3.24 (m, 1H), 3.03 (s, 3H), 1.87-1.74 (m, 2H), 1.31 (dd, 6H, J = 6.7,3.5 Hz) N-{2-[(3S,4R)- 3-fluoro-4- methoxypiperidin- 1-yl]pyrimidin-4-yl}-8-[3- (methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan- 2-yl)-2,6-naphthyridin-3- amine 75

544 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.55 (s, 1H), 9.11 (s, 1H), 8.70(s, 1H), 8.50 (s, 1H), 7.48 (d, 1H, J = 8.0 Hz), 6.48 (d, 1H, J = 8.1Hz), 5.00 (d, 1H, J = 49.1 Hz), 4.77 (s, 1H), 4.52 (d, 1H, J = 13.5 Hz),4.41 (t, 2H, J = 7.7 Hz), 3.99 (t, 2H, J = 6.9 Hz), 3.73-3.45 (m, 6H),3.38-3.33 (m, 4H), 3.02 (s, 3H), 1.92-1.84 (m, 1H), 1.83-1.73 (m, 1H),1.31 (dd, 6H, J = 6.8, 5.0 Hz) N-{3-[(3S,4R)- 3-fluoro-4-methoxypiperidin- 1-yl]-1,2,4- triazin-5-yl}-8-[3- (methanesulfonyl-methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine 76

544 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.54 (s, 1H), 9.11 (s, 1H), 8.69(s, 1H), 8.49 (s, 1H), 7.47 (d, 1H, J = 8.0 Hz), 6.47 (d, 1H, J = 8.1Hz), 4.99 (d, 1H, J = 49.0 Hz), 4.79-4.73 (m, 1H), 4.51 (d, 1H, J = 13.5Hz), 4.40 (t, 2H, J = 7.7 Hz), 3.98 (t, 2H, J = 6.9 Hz), 3.70-3.42 (m,7H), 3.37-3.23 (m, 3H), 3.01 (s, 3H), 1.90- 1.83 (m, 1H), 1.81-1.71 (m,1H), 1.30 (dd, 6H, J = 6.8, 3.7 Hz) N-{3-[(3R,4S)- 3-fluoro-4-methoxypiperidin- 1-yl]-1,2,4- triazin-5-yl}-8-[3- (methanesulfonyl-methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine 77

545 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.01 (s, 1H), 8.86(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.00 (d, 1H, J = 8.3 Hz), 6.46- 6.26(m, 2H), 5.01 (d, 1H, J = 6.4 Hz), 4.76 (dd, 2H, J = 22.7, 10.0 Hz),4.39-4.23 (m, 2H), 4.02-3.71 (m, 5H), 3.57 (d, 3H, J = 7.5 Hz),3.31-3.19 (m, 2H), 3.13 (q, 3H, J = 7.5 Hz), 1.88-1.62 (m, 2H), 1.38 (d,3H, J = 21.2 Hz), 1.25 (t, 3H, J = 7.4 Hz) NN; Peak 1 (3S,4R)-1-{4-[(8-{3-[(ethane- sulfonyl)methyl] azetidin-1-yl}-5- methoxyiso-quinolin-3-yl) amino]pyrimidin- 2-yl}-3-fluoro-3- methylpiperidin- 4-ol78

545 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.02 (s, 1H), 8.66(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.01 (d, 1H, J = 8.3 Hz), 6.43 (d,1H, J = 5.7 Hz), 6.37 (d, 1H, J = 8.3 Hz), 4.99 (d, 1H, J = 6.4 Hz),4.78 (dd, 1H, J = 14.0, 8.8 Hz), 4.68 (d, 1H, J = 13.1 Hz), 4.30 (t, 2H,J = 7.4 Hz), 4.17 (q, 2H, J = 6.9 Hz), 3.86 (t, 2H, J = 6.8 Hz), 3.59(d, 2H, J = 7.3 Hz), 3.56-3.42 (m, 1H), 3.31-3.04 (m, 3H), 3.02 (s, 3H),1.75-1.68 (m, 2H), 1.52-1.18 (m, 6H) NN; Peak 1 (3S,4R)-1-[4-({5-ethoxy-8-[3- (methanesulfonyl- methyl)azetidin- 1-yl]isoquinolin-3-yl}amino) pyrimidin-2-yl]- 3-fluoro-3- methylpiperidin- 4-ol 79

545 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.02 (d, 1H, J = 0.9Hz), 8.81 (s, 1H), 7.98 (d, 1H, J = 5.7 Hz), 7.00 (d, 1H, J = 8.4 Hz),6.42-6.33 (m, 2H), 5.11 (d, 1H, J = 5.4 Hz), 4.76 (d, 1H, J = 49.8 Hz),4.42-4.14 (m, 3H, J = 7.5 Hz), 4.09- 3.71 (m, 7H), 3.59 (d, 2H, J = 7.4Hz), 3.55-3.40 (m, 2H), 3.26 (t, 1H, J = 7.3 Hz), 3.02 (s, 3H),0.99-0.90 (m, 6H) J; Peak 2 (4S,5R)-5-fluoro- 1-[4-({8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-5-methoxy- isoquinolin-3-yl}amino)pyrimidin- 2-yl]-3,3- dimethyl- piperidin-4-ol or(4R,5S)-5-fluoro- 1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-methoxy- isoquinolin-3-yl} amino)pyrimidin-

2-yl]-3,3- dimethyl- piperidin-4-ol 80

546 1H NMR (400 MHz, DMSO- d6) δ 10.09 (s, 1H), 8.99 (s, 1H), 8.54 (s,1H), 8.01 (d, J = 5.6 Hz, 1H), 7.73 (s, 1H), 6.45 (d, J = 5.8 Hz, 1H),4.96 (d, J = 6.4 Hz, 1H), 4.81- 4.58 (m, 2H), 4.47 (d, J = 8.5 Hz, 2H),4.22-4.07 (m, 4H), 3.64-3.45 (m, 3H), 3.20-3.04 (m, 2H), 2.99 (s, 3H),1.76- 1.60 (m, 2H), 1.45-1.18 (m, 8H). NN; Peak 1 (3S,4R)-1-[4-({5-ethoxy-8-[3- (methanesulfonyl- methyl)azetidin- 1-yl]-2,7-naph-thyridin-3-yl} amino)pyrimidin- 2-yl]-3-fluoro-3- methyl- piperidin-4-ol81

546 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.03 (s, 1H), 8.60(s, 1H), 7.98 (d, 1H, J = 5.7 Hz), 7.40 (d, 1H, J = 7.9 Hz), 6.46 (d,1H, J = 5.7 Hz), 6.39 (d, 1H, J = 8.1 Hz), 4.92 (d, 1H, J = 49.6 Hz),4.75-4.69 (m, 1H), 4.47 (d, 1H, J = 13.2 Hz), 4.37 (t, 2H, J = 7.5 Hz),3.95-3.93 (m, 2H), 3.67-3.44 (m, 6H), 3.00 (s, 3H), 1.81- 1.75 (m, 2H),1.28 (d, 6H, J = 3.3 Hz) K; Peak 1 N-{2-[(3R,4S)-3- fluoro-4-(²H3)methoxy- piperidin-1-yl] pyrimidin-4-yl}- 8-[3-(methane- sulfonylmethyl)azetidin-1-yl]-5- (propan-2-yl) isoquinolin-3- amine 82

546 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.03 (s, 1H), 8.60(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.40 (d, 1H, J = 7.9 Hz), 6.45 (d,1H, J = 5.7 Hz), 6.39 (d, 1H, J = 8.0 Hz), 4.92 (d, 1H, J = 49.4 Hz),4.75-4.69 (m, 1H), 4.47 (d, 1H, J = 12.3 Hz), 4.37 (t, 2H, J = 7.6 Hz),3.94 (t, 2H, J = 6.9 Hz), 3.66-3.43 (m, 6H), 3.00 (s, 3H), 1.81-1.69 (m,2H), 1.28 (dd, 6H, J = 6.7, 3.2 Hz) K; Peak 2 N-{2-[(3S,4R)- 3-fluoro-4-(²H3)methoxy- piperidin-1-yl] pyrimidin-4-yl}- 8-[3-(methane-sulfonylmethyl) azetidin-1-yl]-5- (propan-2-yl) isoquinolin-3- amine 83

547 1H NMR (400 MHz, DMSO- d6) δ 10.11 (s, 1H), 9.11 (s, 1H), 8.71 (s,1H), 8.03 (d, J = 5.6 Hz, 1H), 7.37 (dd, 1H, J = 10.4, 8.3 Hz), 6.48(dd, 1H, J = 8.6, 4.0 Hz), 6.42 (d, 1H, J = 5.6 Hz), 5.12 (d, 1H, J =5.4 Hz), 4.76-4.63 (m, 2H), 4.31-4.15 (m, 1H), 3.88 (d, 2H, J = 13.4Hz), 3.69 (t, 1H, J = 7.1 Hz), 3.56 (td, 2H, J = 14.7, 14.2, 7.6 Hz),3.43 (d, 1H, J = 13.8 Hz), 3.02 (s, 3H), 2.91 (q, 1H, J = 7.3 Hz), 1.44(d, 3H, J = 6.0 Hz), 1.03-0.95 (m, 6H). J; Peak 2 (4S,5R)-5-fluoro-1-[4-({5-fluoro- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]isoquinolin-3- yl}amino) pyrimidin-2-yl]-3,3-dimethyl- piperidin-4-ol or (4R,5S)-5-fluoro- 1-[4-({5-fluoro-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-

yl]isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3,3-dimethyl-piperidin-4-ol 84

547 ¹H NMR (400 MHz, DMSO- d₆) δ 10.12 (s, 1H), 9.12 (d, J = 1.7 Hz,1H), 8.70 (s, 1H), 8.04 (d, J = 5.6 Hz, 1H), 7.38 (dd, J = 10.4, 8.4 Hz,1H), 6.52-6.40 (m, 2H), 4.84-4.64 (m, 3H), 4.24 (p, J = 6.1 Hz, 1H),3.70 (t, J = 7.1 Hz, 1H), 3.66-3.49 (m, 2H), 3.40 (s, 4H), 3.30-3.05 (m,2H), 3.03 (s, 3H), 2.92 (h, J = 7.2 Hz, 1H), 2.07-1.96 (m, 1H), 1.63 (d,J = 13.2 Hz, 1H), 1.45 (dd, J = 13.6, 7.6 Hz, 6H). NN; Peak 15-fluoro-N-{2- [(3S,4R)-3- fluoro-4- methoxy-3- methylpiperidin-1-yl]pyrimidin- 4-yl}-8- [(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]isoquinolin-3- amine 85

547 1H NMR (400 MHz, DMSO- d6) δ 10.13 (s, 1H), 9.12 (s, 1H), 8.68 (s,1H), 8.05 (d, 1H, J = 5.5 Hz), 7.36 (dd, 1H, J = 10.3, 8.4 Hz), 6.48(dd, 2H, J = 7.2, 4.0 Hz), 4.96 (d, 1H, J = 50.3 Hz), 4.71 (t, 2H, J =7.4 Hz), 4.47 (d, J = 13.6 Hz, 1H), 4.24 (p, J = 6.2 Hz, 1H), 3.69 (t, J= 7.1 Hz, 1H), 3.66-3.42 (m, 4H), 3.38 (s, 3H), 3.31-3.23 (m, 1H), 3.12(q, J = 7.4 Hz, 2H), 2.91 (q, J = 7.3 Hz, 1H), 1.94- 1.68 (m, 2H), 1.45(d, J = 6.0 Hz, 3H), 1.26 (t, J = 7.4 Hz, 3H). 8-[(2R,3S)-3-[(ethanesulfonyl) methyl]-2- methylazetidin- 1-yl]-5-fluoro-N-{2-[(3S,4R)- 3-fluoro-4- methoxy- piperidin-1-yl] pyrimidin-4-yl}isoquinolin-3- amine 86

551 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.67 (s, 1H), 8.08 (d, J =5.6 Hz, 1H), 7.34 (s, 1H), 7.08 (dd, J = 13.2, 9.6 Hz, 1H), 6.09 (d, J =5.6 Hz, 1H), 5.14- 4.95 (m, 1H), 4.94-4.80 (m, 1H), 4.70-4.61 (m, 2H),4.34-4.22 (m, 3H), 4.17-4.07 (m, 1H), 3.79-3.64 (m, 3H), 3.51-3.46 (m,2H), 3.44-3.35 (m, 1H), 2.99 (s, 3H), 1.13 (s, 3H), 1.06 (s, 3H) J; Peak2 (4S,5R)-1-[4- ({5,7-difluoro- 8-[3-(methane- sulfonylmethyl)azetidin-1-yl] isoquinolin-3- yl}amino) pyrimidin-2-yl]- 5-fluoro-3,3-dimethyl- piperidin-4-ol or (4R,5S)-1-[4- ({5,7-difluoro- 8-[3-(methane-sulfonylmethyl) azetidin-1-yl] isoquinolin-3- yl}amino)

pyrimidin-2-yl]- 5-fluoro-3,3- dimethyl- piperidin-4-ol 87

553 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.82 (s, 1H), 9.02 (s, 1H), 8.63(s, 1H), 7.97 (d, 1H, J = 5.6 Hz), 7.36 (d, 1H, J = 8.0 Hz), 6.40 (dd,2H, J = 10.8, 6.9 Hz), 4.71 (t, 1H, J = 5.0 Hz), 4.53-4.24 (m, 4H),4.03-3.81 (m, 4H), 3.79-3.66 (m, 3H), 3.65-3.48 (m, 3H), 3.41 (q, 1H, J= 6.7 Hz), 3.27-3.20 (m, 1H), 3.00 (s, 3H), 2.39 (t, 2H, J = 7.7 Hz),1.99-1.70 (m, 4H), 1.26 (d, 3H, J = 6.6 Hz) F; Peak 2 (2S)-2-{8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-3-[(2-{1- oxa-7-azaspiro[3,5]nonan-7-yl} pyrimidin-4-yl) amino] isoquinolin-5-yl} propan-1-ol or(2R)-2-{8-[3- (methanesulfonyl- methyl)azetidin- 1-yl]-3-[(2-{1-oxa-7-azaspiro [3.5]nonan-7-yl} pyrimidin-4-yl) amino]

isoquinolin-5-yl} propan-1-ol 88

553 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.86 (s, 1H), 9.02 (s, 1H), 7.99(d, 1H, J = 5.6 Hz), 7.39 (d, 1H, J = 8.0 Hz), 6.46 (d, 1H, J = 5.7 Hz),6.39 (d, 1H, J = 8.2 Hz), 4.37 (t, 2H, J = 7.7 Hz), 3.92 (d, 10H, J =10.9 Hz), 3.57 (d, 2H, J = 7.3 Hz), 3.43 (t, 1H, J = 6.8 Hz), 3.29-3.21(m, 1H), 3.00 (s, 3H), 1.73- 1.59 (m, 4H), 1.26 (d, 6H, J = 6.7 Hz)N-(2-{1,4-dioxa- 8-azaspiro[4.5] decan-8-yl} pyrimidin-4-yl)-8-[3-(methane- sulfonylmethyl) azetidin-1-yl]- 5-(propan-2-yl)isoquinolin- 3-amine 89

554 1H-NMR (400 MHz, 4d- CD3OD) δ ppm 9.10 (s, 1H), 8.56 (s, 1H), 7.97(d, 1H, J = 5.8 Hz), 7.46 (d, 1H, J = 8.0 Hz), 6.64 (d, 1H, J = 8.0 Hz),6.42 (d, 1H, J = 5.8 Hz), 4.76-4.60 (m, 3H), 4.27 (t, 1H, J = 6.3 Hz),3.67-3.46 (m, 4H), 3.45 (s, 3H), 3.18 (t, 2H, J = 9.9 Hz), 3.00 (s, 3H),3.06-2.86 (m, 2H), 2.80-2.71 (m, 1H), 2.26-2.16 (m, 1H), 1.54-1.28 (m,10H) D; Peak 1 N-{2-[(3S,4S)- 3-amino-4- methoxy- piperidin-1-yl]pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine 90

555 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.88 (s, 1H), 9.05 (s, 1H), 8.70(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.23 (d, 1H, J = 7.9 Hz), 6.55- 6.42(m, 2H), 4.98 (t, 1H, J = 7.2 Hz), 4.78-4.62 (m, 3H), 4.19 (p, 1H, J =6.4 Hz), 3.64 (t, 1H, J = 7.0 Hz), 3.60-3.51 (m, 2H), 3.53-3.40 (m, 1H),3.19-3.03 (m, 2H), 2.99 (s, 3H), 2.88 (q, 1H, J = 7.3 Hz), 2.12 (td, 1H,J = 8.4, 4.1 Hz), 1.75-1.57 (m, 2H), 1.45-1.36 (m, 3H), 1.31 (d, 3H, J =21.2 Hz), 0.97 (dd, 2H, J = 8.2, 4.1 Hz), 0.71-0.58 (m, 2H) L; Peak 1(3S,4R)-1-[4- ({5-cyclopropyl- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]isoquinolin-3- yl}amino)pyrimidin-2-yl]- 3-fluoro-3- methylpiperidin- 4-ol 91

555 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.82 (s, 1H), 9.04 (s, 1H), 8.67(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.47- 6.36(m, 2H), 4.61 (d, 1H, J = 5.0 Hz), 4.39 (t, 2H, J = 7.6 Hz), 3.96 (t,4H, J = 6.9 Hz), 3.85-3.62 (m, 3H), 3.61-3.42 (m, 4H), 3.37 (s, 3H),3.36-3.30 (m, 1H), 3.12 (q, 2H, J = 7.4 Hz), 1.92-1.86 (m, 1H),1.66-1.60 (m, 1H), 1.40-1.06 (m, 9H) K; Peak 1 (3S,4R)-1-{4-[(8-{3-[(ethane- sulfonyl)methyl] azetidin-1-yl}-5- (propan-2-yl)isoquinolin-3-yl) amino]pyrimidin- 2-yl}-4- methoxy- piperidin-3-ol or(3R,4S)-1-{4- [(8-{3-[(ethane- sulfonyl)methyl] azetidin-1-yl}-5-(propan-2-yl) isoquinolin-3-yl) amino]pyrimidin-

2-yl}-4-methoxy- piperidin-3-ol 92

555 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.87 (s, 1H), 9.05 (s, 1H), 8.66(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.45 (d, 1H, J = 5.7 Hz), 5.08 (d, 1H, J = 4.8 Hz),4.66 (t, 1H, J = 7.5 Hz), 4.46-4.30 (m, 2H), 4.20 (t, 1H, J = 6.3 Hz),3.64 (t, 1H, J = 7.1 Hz), 3.54 (t, 3H, J = 6.8 Hz), 3.39 (s, 3H),3.29-3.19 (m, 2H), 3.22-3.07 (m, 1H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.2Hz), 2.11-2.01 (m, 1H), 1.43 (d, 3H, J = 6.0 LL, Peak 1(3S,4S)-1-[4-({8- [(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol or (3R,4R)-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-

Hz), 1.30 (dd, 6H, J = 6.7, 3.2 Hz) yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol 93

555 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.83 (s, 1H), 9.03 (s, 1H), 8.67(s, 1H), 7.96 (d, 1H, J = 5.6 Hz), 7.40 (d, 1H, J = 7.9 Hz), 6.54 (d,1H, J = 8.0 Hz), 6.40 (d, 1H, J = 5.7 Hz), 4.62 (dd, 2H, J = 17.2, 6.3Hz), 4.17 (t, 1H, J = 6.2 Hz), 3.95 (s, 2H), 3.82-3.42 (m, 8H), 3.35 (s,3H), 2.98 (s, 3H), 2.87 (q, 1H, J = 7.3 Hz), 1.88-1.82 (m, 1H),1.64-1.58 (m, 1H), 1.41 (d, 3H, J = 6.0 Hz), 1.28 (d, 6H, J = 6.6 Hz)JJ, Peak 1 (3S,4R)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol or (3R,4S)-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-

yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methoxy-piperidin-3-ol 94

555 1H-NMR (300 MHz, 4d- CD3OD) δ ppm 9.11 (s, 1H), 8.67 (s, 1H), 7.96(d, 1H, J = 5.8 Hz), 7.48 (d, 1H, J = 8.0 Hz), 6.53 (d, 1H, J = 8.0 Hz),6.34 (d, 1H, J = 5.8 Hz), 4.63-4.37 (m, 5H), 4.03 (td, 2H, J = 7.6, 6.9,1.9 Hz), 3.73-3.57 (m, 4H), 3.48-3.33 (m, 2H), 3.23 (s, 3H), 3.17 (d,1H, J = 13.9 Hz), 3.04 (s, 3H), 1.96 (ddt, 1H, J = 13.8, 10.0, 5.0 Hz),1.82-1.70 (m, 1H), 1.43-1.25 (m, 9H) L; Peak 1 (3R,4S)-1-[4- ({8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 3-methoxy-3- methylpiperidin- 4-ol or(3S,4R)- 1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)isoquinolin-

3-yl}amino) pyrimidin-2-yl]- 3-methoxy-3- methyl- piperidin-4-ol 95

555 1H-NMR (300 MHz, 4d- CD3OD) δ ppm 9.11 (s, 1H), 8.67 (s, 1H), 7.96(d, 1H, J = 5.8 Hz), 7.48 (d, 1H, J = 8.0 Hz), 6.53 (d, 1H, J = 8.0 Hz),6.34 (d, 1H, J = 5.8 Hz), 4.58 (d, 2H, J = 15.2 Hz), 4.43 (td, 2H, J =7.6, 2.1 Hz), 4.08-3.97 (m, 2H), 3.73- 3.57 (m, 4H), 3.39 (d, 3H, J =10.2 Hz), 3.23 (s, 3H), 3.16 (d, 1H, J = 13.9 Hz), 3.04 (s, 3H), 1.96(ddt, 1H, J = 13.9, 9.8, 4.9 Hz), 1.82- 1.70 (m, 1H), 1.38 (t, 6H, L;Peak 2 (3S,4R)-1-[4- ({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]-3-methoxy-3- methylpiperidin- 4-ol or (3R,4S)- 1-[4-({8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin-

J = 6.7 Hz), 1.27 (s, 3H) 3-yl}amino) pyrimidin-2-yl]- 3-methoxy-3-methylpiperidin- 4-ol 96

555 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.90 (s, 1H), 9.06 (s, 1H), 8.67(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 7.9 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.44 (d, 1H, J = 5.7 Hz), 5.01 (d, 1H, J = 4.3 Hz),4.66 (t, 1H, J = 7.5 Hz), 4.24-4.14 (m, 2H), 4.06 (s, 1H), 3.77-3.39 (m,7H), 3.35 (s, 3H), 3.11-3.03 (m, 1H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.2Hz), 1.90-1.84 (m, 1H), 1.57-1.39 (m, 4H), 1.30 (dd, 6H, J = 6.7, 2.5Hz) D; Peak 1 (3S,4S)-1-[4-({8- [(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 3-methoxy- piperidin-4-ol or (3R,4R)-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-

yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methoxy-piperidin-4-ol 97

555 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.05 (s, 1H), 8.67(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.43 (d, 1H, J = 5.7 Hz), 4.66 (dd, 2H, J = 6.0, 3.3Hz), 4.19 (t, 1H, J = 6.3 Hz), 4.04 (dd, 1H, J = 13.1, 7.2 Hz), 3.95 (s,2H), 3.79 (d, 2H, J = 13.0 Hz), 3.64 (t, 1H, J = 7.2 Hz), 3.53 (h, 3H, J= 7.2 Hz), 3.33-3.25 (m, 4H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.2 Hz),1.81-1.57 (m, 2H), 1.43 D; Peak 2 (3S,4R)-1-[4- ({8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methoxy- piperidin-4-olor (3R,4S)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1-

(d, 3H, J = 6.0 Hz), 1.30 (dd, 6H, J = 6.7, 1.6 Hz) yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methoxy- piperidin-4-ol98

555 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.91 (s, 1H), 9.06 (s, 1H), 8.66(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.44 (d, 1H, J = 5.7 Hz), 5.01 (d, 1H, J = 4.3 Hz),4.66 (t, 1H, J = 7.5 Hz), 4.35-4.00 (m, 3H), 3.73-3.41 (m, 7H), 3.35 (s,3H), 3.09-3.02 (m, 1H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.2 Hz),1.89-1.83 (m, 1H), 1.54-1.39 (m, 4H), 1.30 (dd, 6H, J = 6.8, 4.8 Hz) D;Peak 1 (3R,4R)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 3-methoxy- piperidin-4-ol or (3S,4S)-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-

yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methoxy-piperidin-4-ol 99

555 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.90 (s, 1H), 9.05 (s, 1H), 8.68(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.0 Hz), 6.43 (d, 1H, J = 5.7 Hz), 4.72-4.61 (m, 2H), 4.19 (t,1H, J = 6.2 Hz), 4.13-3.89 (m, 4H), 3.75 (d, 2H, J = 13.2 Hz), 3.64 (t,1H, J = 7.3 Hz), 3.53 (h, 3H, J = 7.3 Hz), 3.30 (s, 3H), 3.00 (s, 3H),2.88 (p, 1H, J = 7.2 Hz), 1.82-1.53 (m, 2H), 1.43 (d, 3H, J = 6.0 Hz),1.30 (d, 6H, J = 6.7 Hz) D; Peak 2 (3R,4S)-1-[4- ({8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methoxy- piperidin-4-olor (3S,4R)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1-

yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methoxy-piperidin-4-ol 100

555 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.87 (s, 1H), 9.05 (s, 1H), 8.69(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.42 (d, 1H, J = 5.7 Hz), 4.72-4.60 (m, 2H), 4.44 (dt,2H, J = 17.1, 8.6 Hz), 4.24-4.15 (m, 2H), 3.64 (t, 1H, J = 7.3 Hz),3.62-3.44 (m, 3H), 3.35-3.18 (m, 2H), 3.07 (t, 1H, J = 11.2 Hz), 3.00(s, 3H), 2.89 (q, 1H, J = 7.2 Hz), 1.72-1.47 (m, 2H), 1.43 (d, 3H, J =6.0 Hz), 1.30 (dd, 6H, J = 6.7, 4.3 F; Peak 1 (3R,4S)-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methyl-piperidine-3,4- diol or (3S,4R)- 1-[4-({8- [(2R,3S)-3- (methanesulfonyl-methyl)-2-

Hz), 1.18 (s, 3H) methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 4-methyl- piperidine-3,4- diol 101

555 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.88 (s, 1H), 9.05 (s, 1H), 8.68(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.42 (d, 1H, J = 5.6 Hz), 4.66 (s, 2H), 4.44 (dt, 2H, J= 16.5, 8.3 Hz), 4.21-4.15 (m, 2H), 3.69-3.44 (m, 4H), 3.30-3.17 (m,2H), 3.07 (t, 1H, J = 11.2 Hz), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.3 Hz),1.66 (d, 1H, J = 13.4 Hz), 1.53 (d, 1H, J = 12.8 Hz), 1.42 (d, 3H, J =6.0 Hz), 1.30 (t, 6H, J = F; Peak 2 (4R)-1-[4-({8- [(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methyl- piperidine-3,4-diol or (3S,4R)- 1-[4-({8- [(2R,3S)-3- (methanesulfonyl- methyl)-2-

6.6 Hz), 1.19 (s, 3H) methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methyl- piperidine-3,4-diol 102

555 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.86 (s, 1H), 9.05 (s, 1H), 8.73(s, 1H), 7.97 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.39 (d, 1H, J = 5.7 Hz), 4.77 (d, 1H, J = 5.1 Hz),4.66 (t, 1H, J = 7.5 Hz), 4.51 (s, 1H), 4.24-4.14 (m, 1H), 3.96 (d, 2H,J = 20.1 Hz), 3.79 (d, 1H, J = 10.8 Hz), 3.71-3.37 (m, 6H), 3.00 (s,3H), 2.93-2.82 (m, 1H), 1.80-1.71 (m, 1H), 1.52-1.37 (m, 4H), 1.34-1.21(m, 6H), 1.16 (s, 3H) D; Peak 2 (3R,4R)-1-[4- ({8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methyl- piperidine-3,4-diol or (3S,4S)- 1-[4-({8- [(2R,3S)-3- (methanesulfonyl- methyl)-2-

methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 4-methyl- piperidine-3,4- diol 103

556 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.08 (s, 1H), 9.10 (s, 1H), 8.78(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.70 (s, 1H), 6.39 (d, 1H, J = 5.6Hz), 4.71 (t, 1H, J = 7.6 Hz), 4.62 (d, 1H, J = 4.9 Hz), 4.29 (t, 1H, J= 6.3 Hz), 3.99 (s, 2H), 3.83-3.49 (m, 7H), 3.45 (d, 1H, J = 7.8 Hz),3.34 (s, 3H), 2.98 (s, 3H), 2.90 (q, 1H, J = 7.3 Hz), 1.91-1.85 (m, 1H),1.66-1.60 (m, 1H), 1.46 (d, 3H, J = 6.0 Hz), 1.29 (dd, 6H, J = 6.7, 4.3Hz) II, Peak 1 (3S,4R)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)-2,6-naph-thyridin-3-yl} amino)pyrimidin- 2-yl]-4- methoxy- piperidin-3-ol or(3R,4S)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-

methylazetidin-1- yl]-5-(propan-2- yl)-2,6-naph- thyridin-3-yl}amino)pyrimidin- 2-yl]-4- methoxy- piperidin-3-ol 104

556 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.13 (s, 1H), 9.13 (s, 1H), 8.78(s, 1H), 8.03 (d, 1H, J = 5.6 Hz), 7.73 (s, 1H), 6.44 (d, 1H, J = 5.6Hz), 5.11 (d, 1H, J = 4.7 Hz), 4.74 (t, 1H, J = 7.6 Hz), 4.44- 4.26 (m,3H), 3.74 (dt, 2H, J = 14.2, 7.1 Hz), 3.54 (dt, 2H, J = 14.0, 6.7 Hz),3.47- 3.41 (m, 1H), 3.39 (s, 3H), 3.30-3.11 (m, 3H), 3.01 (s, 3H), 2.93(q, 1H, J = 7.3 Hz), 2.08-2.02 (m, 1H), 1.48 (d, 3H, J = 6.0 Hz),1.42-1.35 (m, 1H), 1.31 (dd, 6H, J = HH, Peak 1 (3S,4S)-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)-2,6-naph- thyridin-3-yl} amino)pyrimidin- 2-yl]-4-methoxy- piperidin-3-ol or (3R,4R)-1-[4- ({8-[(2R,3S)-3-(methanesulfonyl- methyl)-2-

8.9, 6.6 Hz) methylazetidin-1- yl]-5-(propan-2- yl)-2,6-naph-thyridin-3-yl} amino)pyrimidin- 2-yl]-4- methoxy- piperidin-3-ol 105

556 1H NMR (400 MHz, DMSO- d6) δ 10.07 (s, 1H), 9.06 (s, 1H), 8.60 (s,1H), 8.08-8.01 (m, 2H), 6.49 (d, 1H, J = 5.6 Hz), 4.88 (t, 1H, J = 8.0Hz), 4.63 (d, 1H, J = 5.1 Hz), 4.58 (t, 1H, J = 6.2 Hz), 4.08-3.91 (m,2H), 3.82 (s, 1H), 3.75 (s, 1H), 3.60-3.53 (m, 2H), 3.49 (d, 1H, J = 7.4Hz), 3.40 (s, 3H), 3.02 (s, 3H), 2.96-2.87 (m, 1H), 1.92-1.85 (m 1H),1.66 (s, 1H), 1.52 (d, 3H, J = 6.2 Hz), 1.35 (dd, 6H, J = 6.8, 4.6 Hz),1.27 (s, 3H). JJ, Peak 1 (3S,4R)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph-thyridin-3-yl} amino)pyrimidin- 2-yl]-4- methoxy- piperidin-3-ol or(3R,4S)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-

methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-yl}amino)pyrimidin- 2-yl]-4- methoxy- piperidin-3-ol 106

556 1H NMR (400 MHz, DMSO- d6) δ 10.09 (s, 1H), 9.06 (s, 1H), 8.57 (s,1H), 8.06 (d, 1H, J = 5.6 Hz), 8.02 (s, 1H), 6.52 (d, J = 5.6 Hz, 1H),5.10 (d, J = 4.9 Hz, 1H), 4.88 (t, J = 8.0 Hz, 1H), 4.58 (t, J = 6.2 Hz,1H), 4.47-4.26 (m, 2H), 4.00 (t, J = 7.3 Hz, 1H), 3.64-3.49 (m, 2H),3.41 (s, 5H), 3.30-3.12 (m, 2H), 3.02 (s, 3H), 2.92 (q, J = 7.3 Hz, 1H),2.13-2.02 (m, 1H), 1.52 (d, J = 6.1 Hz, 3H), 1.45-1.21 (m, 8H). LL, Peak1 (3S,4S)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-yl}amino)pyrimidin- 2-yl]-4- methoxy- piperidin-3-ol or (3R,4R)-1-[4-({8-[(2R,3S)-3- (methanesulfonyl-

methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph-thyridin-3-yl} amino)pyrimidin- 2-yl]-4- methoxy- piperidin-3-ol 107

556 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.06 (s, 1H), 8.64(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 7.9 Hz), 6.56 (d,1H, J = 8.0 Hz), 6.47 (d, 1H, J = 5.7 Hz), 4.95 (d, 1H, J = 49.5 Hz),4.81-4.69 (m, 1H), 4.64 (t, 1H, J = 7.5 Hz), 4.50 (d, 1H, J = 13.3 Hz),4.21-4.13 (m, 1H), 3.70 (d, 2H, J = 9.8 Hz), 3.59-3.38 (m, 6H),3.31-3.20 (m, 3H), 2.94-2.90 (m, 4H), 1.87-1.67 (m, 2H), 1.42 (d, 3H, J= 6.0 L; Peak 1 (1S)-(((2R)-1- (6-((2- ((3R,4S)-3- fluoro-4- methoxy-piperidin-1-yl) pyrimidin-4-yl) amino)-4- isopropyl-2,7- naphthyridin-1-yl)-2- methylazetidin- 3-yl)methyl) (imino) (methyl)-λ⁶-

Hz), 1.31 (t, 6H, J = 6.9 Hz) sulfanone or (1R)-(((2R)- 1-(6-((2-((3R,4S)-3- fluoro-4- methoxy- piperidin-1-yl) pyrimidin-4-yl) amino)-4-isopropyl-2,7- naphthyridin- 1-yl)-2- methylazetidin- 3-yl)methyl)(imino) (methyl)-λ⁶- sulfanone 108

556 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.06 (s, 1H), 8.64(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 7.9 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.47 (d, 1H, J = 5.7 Hz), 4.95 (d, 1H, J = 49.0 Hz),4.80-4.70 (m, 1H), 4.66 (t, 1H, J = 7.5 Hz), 4.50 (d, 1H, J = 13.1 Hz),4.25-4.17 (m, 1H), 3.73 (s, 1H), 3.63 (t, 1H, J = 7.1 Hz), 3.55-3.40 (m,7H), 3.35-3.20 (m, 2H), 2.94-2.89 (m, 4H), 1.87-1.70 (m, 2H), 1.43 (d,L; Peak 2 (1S)-(((2R)-1- (6-((2- ((3R,4S)-3- fluoro-4- methoxy-piperidin-1-yl) pyrimidin-4-yl) amino)-4- isopropyl-2,7- naphthyridin-1-yl)-2- methyl- azetidin-3-yl) methyl)(imino) (methyl)-λ⁶-

3H, J = 6.0 Hz), 1.31 (t, 6H, J = 7.1 Hz) sulfanone or (1R)-(((2R)-1-(6-((2- ((3R,4S)-3- fluoro-4- methoxy- piperidin-1-yl) pyrimidin-4-yl)amino)-4- isopropyl-2,7- naphthyridin- 1-yl)-2- methyl- azetidin-3-yl)methyl)(imino) (methyl)-λ⁶- sulfanone 109

557 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.86 (s, 1H), 9.06 (s, 1H), 8.58(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.49 (d,1H, J = 5.6 Hz), 6.41 (d, 1H, J = 8.0 Hz), 5.14 (d, 1H, J = 5.3 Hz),4.89-4.61 (m, 1H), 4.39 (t, 2H, J = 7.6 Hz), 4.27 (d, 1H, J = 19.3 Hz),3.97 (t, 3H, J = 7.0 Hz), 3.82 (d, 1H, J = 12.9 Hz), 3.68-3.18 (m, 6H),3.29 (s, 3H), 1.30 (dd, 6H, J = 6.7, 4.1 Hz), 1.07- 0.76 (m, 6H) J; Peak2 (4S,5R)-5-fluoro- 1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]-3,3-dimethyl- piperidin-4-ol or (4R,5S)-5- fluoro-1-[4- ({8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin-

3-yl}amino) pyrimidin-2-yl]- 3,3-dimethyl- piperidin-4-ol 110

557 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.87 (s, 1H), 9.05 (s, 1H), 8.61(s, 1H), 7.99 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.47 (d,1H, J = 5.7 Hz), 6.41 (d, 1H, J = 8.1 Hz), 5.03 (d, 1H, J = 6.4 Hz),4.86-4.61 (m, 2H), 4.39 (td, 2H, J = 7.7, 2.3 Hz), 4.08-3.88 (m, 2H),3.67-3.41 (m, 4H), 3.32-3.22 (m, 1H), 3.12 (q, 4H, J = 7.5 Hz),1.83-1.65 (m, 2H), 1.49-1.15 (m, 12H) NN; Peak 1 (3S,4R)-1-{4-[(8-{3-[(ethane- sulfonyl)methyl] azetidin-1-yl}-5- (propan-2-yl)isoquinolin-3- yl)amino] pyrimidin-2-yl}- 3-fluoro-3- methyl-piperidin-4-ol 111

557 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.90 (s, 1H), 9.06 (s, 1H), 8.62(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.3 Hz), 6.46 (d, 1H, J = 5.7 Hz), 5.04 (d, 1H, J = 6.4 Hz),4.92-4.47 (m, 3H), 4.20 (t, 1H, J = 6.5 Hz), 3.59 (dt, 5H, J = 28.9, 7.4Hz), 3.26-3.06 (m, 2H), 3.00 (s, 3H), 2.89 (d, 1H, J = 7.5 Hz),1.85-1.64 (m, 2H), 1.50-1.37 (m, 4H), 1.39- 1.20 (m, 8H) L; Peak 1(3S,4R)-3- fluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl}isoquinolin-3- yl}amino)pyrimidin-2-yl]- 3-methyl- piperidin-4-ol 112

557 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.88 (s, 1H), 9.05 (s, 1H), 8.61(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.47 (d,1H, J = 5.7 Hz), 6.40 (d, 1H, J = 8.1 Hz), 5.03 (d, 1H, J = 6.4 Hz),4.83-4.64 (m, 2H), 4.17 (d, 2H, J = 7.4 Hz), 3.98 (d, 2H, J = 7.4 Hz),3.67 (s, 2H), 3.67-3.43 (m, 2H), 3.25-3.05 (m, 2H), 3.04 (s, 3H),1.78-1.70 (m, 2H), 1.66 (s, 3H), 1.47-1.23 (m, 9H) NN; Peak 1 (3S,4R)-3-fluoro-1-[4- ({8-[3- (methanesulfonyl- methyl)-3- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methyl-piperidin-4-ol 113

557 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.06 (s, 1H), 8.61(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.50 (d,1H, J = 5.8 Hz), 6.43 (d, 1H, J = 8.1 Hz), 4.73 (s, 1H), 4.40 (t, 2H, J= 7.6 Hz), 4.28 (dd, 1H, J = 13.4, 7.8 Hz), 4.14 (s, 1H), 3.97 (t, 2H, J= 6.9 Hz), 3.71-3.65 (m, 3H), 3.59 (d, 2H, J = 7.3 Hz), 3.56-3.45 (m,1H), 3.02 (s, 3H), 1.89-1.83 (m, 1H), 1.61-1.55 (m, 1H), 1.39-1.20 (m,12H) B; Peak 2 (3R,4S)-3- fluoro-1-[4- ({8-[3- (methanesulfonyl-methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino)pyrimidin-2-yl]- 3,4-dimethyl- piperidin-4-ol or (3S,4R)-3- fluoro-1-[4-({8-[3- (methanesulfonyl- methyl)azetidin-

1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]-3,4-dimethyl- piperidin-4-ol 114

557 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.83 (s, 1H), 9.05 (s, 1H), 8.62(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.45 (d,1H, J = 5.7 Hz), 6.41 (d, 1H, J = 8.0 Hz), 4.98 (d, 1H, J = 1.7 Hz),4.62 (q, 2H, J = 12.7 Hz), 4.39 (t, 2H, J = 7.4 Hz), 3.97 (t, 2H, J =6.8 Hz), 3.59 (d, 2H, J = 7.3 Hz), 3.55-3.45 (m, 1H), 3.34-3.18 (m, 3H),3.02 (s, 3H), 1.87-1.81 (m, 1H), 1.58-1.47 (m, 1H), 1.40- 1.22 (m, 9H),1.20 (d, 3H, J = 1.6 Hz) F; Peak 2 (3S,4S)-3- fluoro-1-[4- ({8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 3,4-dimethyl- piperidin-4-ol or (3R,4R)-3-fluoro-1-[4- ({8-[3- (methanesulfonyl- methyl)azetidin-

1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]-3,4-dimethyl- piperidin-4-ol 115

557 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.84 (s, 1H), 9.05 (s, 1H), 8.60(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.47 (d,1H, J = 5.7 Hz), 6.41 (d, 1H, J = 8.1 Hz), 4.97 (d, 1H, J = 6.3 Hz),4.68 (s, 1H), 4.58 (s, 1H), 4.39 (td, 2H, J = 7.7, 2.8 Hz), 3.96 (td,2H, J = 6.9, 2.5 Hz), 3.73-3.55 (m, 3H), 3.53-3.44 (m, 1H), 3.30-3.18(m, 2H), 3.01 (s, 3H), 1.92-1.59 (m, 4H), 1.30 (dd, 6H, J = 6.8, 4.6Hz), 0.93 (t, 3H, J = 7.5 Hz) L; Peak 1 (3S,4R)-3-ethyl- 3-fluoro-1-[4-({8-[3- (methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan-2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl] piperidin-4-ol or(3R,4S)-3-ethyl- 3-fluoro-1-[4- ({8-[3- (methanesulfonyl-methyl)azetidin- 1-yl]-5-(propan-

2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl] piperidin-4-ol 116

557 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.77 (s, 1H), 9.05 (s, 1H), 8.52(s, 1H), 7.97 (d, 1H, J = 5.6 Hz), 7.21 (s, 1H), 6.45 (d, 1H, J = 5.7Hz), 5.03 (d, 1H, J = 6.4 Hz), 4.75 (s, 1H), 4.69 (d, 1H, J = 14.1 Hz),4.57 (t, 2H, J = 7.3 Hz), 4.17-4.06 (m, 2H), 3.52 (dd, 4H, J = 19.0, 7.0Hz), 3.16 (t, 3H, J = 15.4 Hz), 3.00 (s, 3H), 2.38 (s, 3H), 1.77-1.71(m, 2H), 1.50-1.14 (m, 9H) NN; Peak 1 (3S,4R)-3-fluoro- 1-[4-({8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-7-methyl-5- (propan-2-yl)isoquinolin-3-yl} amino)pyrimidin- 2-yl]-3-methyl- piperidin-4-ol 117

557 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.95 (s, 1H), 9.06 (s, 1H), 8.67(s, 1H), 8.01 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.47 (d, 1H, J = 5.7 Hz), 4.86 (s, 1H), 4.66 (t, 1H, J= 7.5 Hz), 4.52-4.36 (m, 2H), 4.25-4.14 (m, 2H), 3.69-3.47 (m, 6H), 3.00(s, 3H), 2.89 (q, 1H, J = 7.3 Hz), 1.73-1.67 (m, 1H), 1.62-1.50 (m, 1H),1.43 (d, 3H, J = 6.0 Hz), 1.34- 1.23 (m, 9H) N; Peak 1 (3S,4R)-3-fluoro-1-[4-({8- [(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methyl-piperidin-4-ol 118

557 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.06 (s, 1H), 8.66(s, 1H), 8.01 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.47 (d, 1H, J = 5.7 Hz), 4.86 (s, 1H), 4.67 (t, 1H, J= 7.5 Hz), 4.53-4.06 (m, 4H), 3.70-3.44 (m, 6H), 3.00 (s, 3H), 2.89 (q,1H, J = 7.3 Hz), 1.74- 1.68 (m, 1H), 1.63-1.54 (m, 1H), 1.43 (d, 3H, J =6.0 Hz), 1.35-1.23 (m, 9H) N; Peak 2 (3R,4S)-3-fluoro- 1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methyl-piperidin-4-ol 119

557 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.05 (s, 1H), 8.63(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.0 Hz), 6.45 (d, 1H, J = 5.7 Hz), 5.32 (d, 1H, J = 4.4 Hz),4.65 (t, 1H, J = 7.5 Hz), 4.19 (t, 1H, J = 6.2 Hz), 3.93-3.89 (m, 4H),3.77-3.73 (m, 1H), 3.63 (t, 1H, J = 7.2 Hz), 3.53 (hept, 3H, J = 7.8,7.3 Hz), 2.99 (s, 3H), 2.89 (q, 1H, J = 7.2 Hz), 1.95-1.85 (m, 1H),1.56-1.51 (m, 1H), 1.42 (d, 3H, J = 6.0 Hz), L; Peak 1 (3S,4S)-3-fluoro-1-[4-({8- [(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methyl-piperidin-4-ol or (3R,4R)-3- fluoro-1-[4-({8- [(2R,3S)-3-(methanesulfonyl-

1.35-1.21 (m, 9H) methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methyl- piperidin-4-ol120

557 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.88 (s, 1H), 9.05 (s, 1H), 8.63(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.52-6.43 (m, 1H), 5.32 (d, 1H, J = 4.4 Hz), 4.65 (t,1H, J = 7.5 Hz), 4.19 (t, 1H, J = 6.3 Hz), 4.04-3.82 (m, 4H), 3.75 (s,1H), 3.64 (t, 1H, J = 7.1 Hz), 3.53 (hept, 3H, J = 7.9, 7.3 Hz), 2.99(s, 3H), 2.89 (q, 1H, J = 7.3 Hz), 1.92-1.88 (m, 1H), 1.57-1.51 (m, 1H),1.42 (d, 3H, J = 6.1 Hz), L; Peak 2 (3R,4R)-3-fluoro- 1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methyl-piperidin-4-ol or (3S,4S)-3-fluoro- 1-[4-({8- [(2R,3S)-3-(methanesulfonyl-

1.35-1.21 (m, 9H) methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methyl- piperidin-4-ol121

557 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.05 (s, 1H), 8.66(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.0 Hz), 6.46 (s, 1H), 4.86 (s, 1H), 4.69-4.63 (m, 1H),4.47-4.37 (m, 2H), 4.22-4.16 (m, 2H), 3.69- 3.47 (m, 6H), 2.99 (s, 3H),2.88 (d, 1H, J = 9.7 Hz), 1.73-1.67 (m, 1H), 1.59-1.53 (m, 1H), 1.42 (d,3H, J = 5.9 Hz), 1.33-1.23 (m, 9H) OO, Peak 2 (3R,4S)-3-fluoro-1-[4-({8- [(2R,3R)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methyl-piperidin-4-ol 122

557 1H NMR (400 MHz, DMSO- d6) δ 9.90 (s, 1H), 9.06 (s, 1H), 8.63 (s,1H), 8.00 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d, 1H, J= 8.1 Hz), 6.47 (d, 1H, J = 5.7 Hz), 4.94 (d, 1H, J = 49.3 Hz), 4.69(dt, J = 25.9, 6.4 Hz, 2H), 4.47 (d, 1H, J = 13.2 Hz), 4.27-4.11 (m,1H), 3.72-3.42 (m, 5H), 3.37 (s, 3H), 2.99 (s, 3H), 2.89 (q, 1H, J = 7.3Hz), 1.86-1.65 (m, 2H), 1.42 (d, 3H, J = 6.0 Hz), 1.31 (dd, 6H, J = 6.8,1.9 Hz). N-{2-[(3S,4R)- 3-fluoro-4- methoxy- piperidin-1-yl]pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine 123

557 1H NMR (400 MHz, DMSO- d6) δ 9.94 (s, 1H), 9.09 (s, 1H), 8.66 (s,1H), 8.03 (d, 1H, J = 5.6 Hz), 7.46 (d, 1H, J = 8.0 Hz), 6.60 (d, 1H, J= 8.0 Hz), 6.51 (d, 1H, J = 5.7 Hz), 4.97 (d, 1H, J = 49.2 Hz),4.86-4.63 (m, 2H), 4.51 (d, 1H, J = 13.7 Hz), 4.23 (t, 1H, J = 6.3 Hz),3.73-3.46 (m, 5H), 3.40 (s, 3H), 3.03 (s, 3H), 2.92 (q, 1H, J = 7.4 Hz),1.85-1.79 (m, 2H), 1.46 (d, 3H, J = 6.0 Hz), 1.34 (t, 6H, J = 6.7 Hz).N-{2-[(3R,4S)- 3-fluoro-4- methoxy- piperidin-1-yl] pyrimidin-4-yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine 124

558 1H NMR (300 MHz, 6d- DMSO) δ ppm 10.09 (s, 1H), 9.03 (s, 1H), 8.49(s, 1H), 8.08-7.96 (m, 2H), 6.51 (d, 1H, J = 5.6 Hz), 5.05 (d, 1H, J =6.4 Hz), 4.81-4.51 (m, 4H), 4.22 (t, 2H, J = 7.4 Hz), 3.58 (d, 3H, J =7.4 Hz), 3.11 (q, 4H, J = 7.5 Hz), 1.74 (m, 2H), 1.41-1.19 (m, 12H) NN;Peak 1 (3S,4R)-1-{4- [(8-{3-[(ethane- sulfonyl)methyl] azetidin-1-yl}-5-(propan-2-yl)- 2,7-naph- thyridin-3-yl) amino]pyrimidin-2-yl}-3-fluoro-3- methylpiperidin- 4-ol 126

558 1H NMR (300 MHz, 6d- DMSO) δ ppm 10.05 (s, 1H), 9.03 (s, 1H), 8.46(s, 1H), 8.01 (d, 1H, J = 5.6 Hz), 7.97 (s, 1H), 6.50 (d, 1H, J = 5.6Hz), 5.02 (d, 1H, J = 6.3 Hz), 4.69 (dd, 2H, J = 24.8, 16.9 Hz), 4.49(dt, 2H, J = 16.5, 8.5 Hz), 4.26 (dt, 2H, J = 34.6, 7.8 Hz), 3.71-3.41(m, 2H), 3.29-2.99 (m, 4H), 2.94 (s, 3H), 1.85-1.59 (m, 2H), 1.47-1.11(m, 12H) D; Peak 1 (3S,4R)-3- fluoro-1-{4- [(8-{3-[(1S)-1-methanesulfonyl- ethyl]azetidin-1- yl}-5-(propan- 2-yl)-2,7-naph-thyridin-3-yl) amino] pyrimidin-2-yl}- 3-methyl- piperidin-4-ol 127

558 1H NMR (300 MHz, 6d- DMSO) δ ppm 10.05 (s, 1H), 9.03 (s, 1H), 8.46(s, 1H), 8.01 (d, 1H, J = 5.6 Hz), 7.97 (s, 1H), 6.50 (d, 1H, J = 5.6Hz), 5.02 (d, 1H, J = 6.4 Hz), 4.82-4.58 (m, 2H), 4.48 (dt, 2H, J =17.9, 8.5 Hz), 4.26 (dt, 2H, J = 31.7, 7.8 Hz), 3.56 (dd, 2H, J = 15.6,8.3 Hz), 3.28-3.01 (m, 4H), 2.94 (s, 3H), 1.85-1.59 (m, 2H), 1.53-1.04(m, 12H) D; Peak 2 (3S,4R)-3- fluoro-1-{4- [(8-{3-[(1R)-1-methanesulfonyl- ethyl]azetidin-1- yl}-5-(propan- 2-yl)-2,7-naph-thyridin-3-yl) amino] pyrimidin-2-yl}- 3-methyl- piperidin-4-ol 128

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.09 (s, 1H), 9.02 (s, 1H), 8.48(s, 1H), 8.01 (d, 1H, J = 5.6 Hz), 7.99 (s, 1H), 6.48 (d, 1H, J = 5.6Hz), 5.03 (d, 1H, J = 6.4 Hz), 4.84 (t, 1H, J = 8.0 Hz), 4.69 (dd, 2H, J= 26.4, 14.7 Hz), 4.53 (t, 1H, J = 6.3 Hz), 3.97 (t, 1H, J = 7.3 Hz),3.52 (d, 3H, J = 7.5 Hz), 3.22-3.03 (m, 2H), 2.97 (s, 3H), 2.87 (q, 1H,J = 7.1 Hz), 1.71 (s, 2H), 1.47 (d, 3H, J = 6.1 Hz), 1.41-1.25 (m, 9H)F; Peak 1 (3S,4R)-3- fluoro-1-[4-({8- [(2S,3R)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph-thyridin-3-yl} amino) pyrimidin-2-yl]- 3-methyl- piperidin-4-ol 129

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.13 (s, 1H), 9.14 (s, 1H), 8.73(s, 1H), 8.03 (d, 1H, J = 5.6 Hz), 7.74 (s, 1H), 6.46 (d, 1H, J = 5.7Hz), 5.04 (d, 1H, J = 6.4 Hz), 4.83-4.63 (m, 3H), 4.32 (t, 1H, J = 6.2Hz), 3.75 (dt, 2H, J = 13.7, 7.0 Hz), 3.66- 3.54 (m, 2H), 3.57-3.47 (m,1H), 3.21-3.08 (m, 2H), 3.01 (s, 3H), 2.93 (q, 1H, J = 7.3 Hz),1.79-1.73 (m, 2H), 1.49 (d, 3H, J = 6.0 Hz), 1.43- 1.24 (m, 9H) NN; Peak1 (3S,4R)-3- fluoro-1-[4-({8- [(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)-2,6-naph- thyridin-3-yl} amino)pyrimidin-2-yl]- 3-methyl- piperidin-4-ol 130

558 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.53 (s, 1H), 9.12 (s, 1H), 8.68(s, 1H), 8.48 (s, 1H), 7.48 (d, 1H, J = 8.0 Hz), 6.63 (d, 1H, J = 8.2Hz), 5.08 (d, 1H, J = 6.3 Hz), 4.88-4.54 (m, 3H), 4.21 (t, 1H, J = 6.2Hz), 3.65 (t, 1H, J = 7.2 Hz), 3.59-3.36 (m, 5H), 3.28-3.10 (m, 2H),2.99 (s, 3H), 2.89 (q, 1H, J = 7.2 Hz), 1.80-1.74 (m, 2H), 1.46-1.38 (m,4H), 1.38-1.23 (m, 8H) L; Peak 2 (3S,4R)-3- fluoro-1-[5- ({8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino)-1,2,4- triazin-3-yl]-3- methyl-piperidin-4-ol 131

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.12 (s, 1H), 9.05 (s, 1H), 8.52(s, 1H), 8.05 (d, 1H, J = 5.6 Hz), 8.01 (s, 1H), 6.53 (d, 1H, J = 5.7Hz), 5.11-4.80 (m, 2H), 4.75-4.69 (m, 1H), 4.56 (t, 1H, J = 6.3 Hz),4.51-4.47 (m, 1H), 4.47-4.42 (m, 1H), 3.99 (t, 1H, J = 7.3 Hz),3.71-3.42 (m, 4H), 3.38 (s, 3H), 3.38-3.23 (m, 2H), 2.99 (s, 3H), 2.90(q, 1H, J = 7.1 Hz), 1.87-1.70 (m, 2H), 1.50 (d, 3H, J = 6.1 Hz), 1.33(dt, 6H, J = 6.6, 3.2 Hz) N-{2-[(3R,4S)- 3-fluoro-4- methoxy-piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph-thyridin-3-amine 132

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.12 (s, 1H), 9.05 (s, 1H), 8.52(s, 1H), 8.05 (d, 1H, J = 5.6 Hz), 8.01 (s, 1H), 6.53 (d, 1H, J = 5.7Hz), 5.09-4.80 (m, 2H), 4.75-4.69 (m, 1H), 4.56 (t, 1H, J = 6.3 Hz),4.47 (d, 1H, J = 13.3 Hz), 3.99 (t, 1H, J = 7.4 Hz), 3.71-3.49 (m, 4H),3.47-3.41 (m, 1H), 3.38 (s, 3H), 2.99 (s, 3H), 2.96-2.85 (m, 1H),1.84-1.78 (m, 2H), 1.50 (d, 3H, J = 6.1 Hz), 1.33 (d, 6H, J = 6.8 Hz)N-{2-[(3S,4R)- 3-fluoro-4- methoxy- piperidin-1-yl] pyrimidin-4-yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-amine 133

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.57 (s, 1H), 9.12 (s, 1H), 8.70(s, 1H), 8.49 (s, 1H), 7.47 (d, 1H, J = 8.0 Hz), 6.63 (d, 1H, J = 8.1Hz), 4.99 (d, 1H, J = 49.6 Hz), 4.75 (s, 1H), 4.69 (t, 1H, J = 7.5 Hz),4.51 (d, 1H, J = 13.6 Hz), 4.21 (t, 1H, J = 6.2 Hz), 3.72-3.42 (m, 6H),3.38 (s, 3H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.2 Hz), 1.92-1.71 (m, 2H),1.43 (d, 3H, J = 6.0 Hz), 1.31 (dd, 6H, J = 6.7, 3.8 Hz) N-{3-[(3R,4S)-3-fluoro-4- methoxy- piperidin-1-yl]- 1,2,4-triazin-5- yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- amine 134

558 1H-NMR (300 MHz. 6d- DMSO) δ ppm 10.56 (s, 1H), 9.10 (s, 1H), 8.69(s, 1H), 8.47 (s, 1H), 7.46 (d, 1H, J = 8.0 Hz), 6.61 (d, 1H, J = 8.1Hz), 4.98 (d, 1H, J = 48.4 Hz), 4.83-4.61 (m, 2H), 4.55-4.45 (m, 1H),4.19 (t, 1H, J = 6.3 Hz), 3.74-3.43 (m, 6H), 3.36 (s, 3H), 2.98 (s, 3H),2.88 (q, 1H, J = 7.2 Hz), 1.88-1.71 (m, 2H), 1.41 (d, 3H, J = 6.0 Hz),1.30 (dd, 6H, J = 6.8, 3.8 Hz) N-{3-[(3S,4R)- 3-fluoro-4- methoxy-piperidin-1-yl]- 1,2,4-triazin-5- yl}-8- [(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine135

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.15 (s, 1H), 9.05 (s, 1H), 8.55(s, 1H), 8.10-7.98 (m, 2H), 6.52 (d, 1H, J = 5.6 Hz), 4.90-4.81 (m, 2H),4.55 (t, 1H, J = 6.3 Hz), 4.47-4.41 (m, 2H), 4.32-4.12 (m, 2H), 3.98 (t,1H, J = 7.3 Hz), 3.70-3.38 (m, 4H), 2.99 (s, 3H), 2.89 (q, 1H, J = 7.3Hz), 1.74- 1.68 (m, 1H), 1.64-1.54 (m, 1H), 1.50 (d, 3H, J = 6.1 Hz),1.30 (dd, 9H, J = 15.2, 8.0 Hz) OO; Peak 2 (3R,4S)-3- fluoro-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-yl} amino)pyrimidin-2-yl]-4-methyl- piperidin-4-ol 136

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.34 (s, 1H), 9.16 (s, 1H), 8.76(s, 1H), 8.05 (d, 1H, J = 5.9 Hz), 7.75 (s, 1H), 6.52 (s, 1H), 4.92 (s,1H), 4.75 (t, 1H, J = 7.6 Hz), 4.55-4.05 (m, 4H), 3.81- 3.52 (m, 6H),3.01 (s, 3H), 2.93 (q, 1H, J = 7.1 Hz), 1.80-1.56 (m, 2H), 1.49 (d, 3H,J = 6.0 Hz), 1.36-1.21 (m, 9H) OO; Peak 2 (3R,4S)-3- fluoro-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)-2,6-naph- thyridin-3-yl} amino)pyrimidin-2-yl]-4-methyl- piperidin-4-ol 137

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.15 (s, 1H), 9.05 (s, 1H), 8.55(s, 1H), 8.06 (d, 1H, J = 5.6 Hz), 8.01 (s, 1H), 6.52 (d, 1H, J = 5.6Hz), 4.90-4.81 (m, 2H), 4.55 (t, 1H, J = 6.3 Hz), 4.47-4.41 (m, 2H),4.32-4.12 (m, 2H), 3.98 (t, 1H, J = 7.3 Hz), 3.65-3.60 (m, 1H),3.60-3.46 (m, 3H), 2.99 (s, 3H), 2.89 (q, 1H, J = 7.3 Hz), 1.74-1.68 (m,1H), 1.62-1.46 (m, 4H), 1.30 (dd, 9H, J = 15.2, 8.0 Hz) OO; Peak 1(3S,4R)-3- fluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-yl}amino)pyrimidin- 2-yl]-4-methyl- piperidin-4-ol 138

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.16 (s, 1H), 8.76 (s, 1H), 8.05(d, 1H, J = 5.9 Hz), 7.75 (s, 1H), 6.52 (s, 1H), 5.01-4.82 (m, 1H), 4.75(t, 1H, J = 7.6 Hz), 4.54-4.03 (m, 4H), 4.14 (s, 1H), 3.87-3.43 (m, 6H),3.01 (s, 3H), 2.98-2.85 (m, 1H), 1.81-1.54 (m, 2H), 1.49 (d, 3H, J = 6.0Hz), 1.34-1.24 (m, 9H) OO; Peak 1 (3S,4R)-3- fluoro-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)-2,6-naph- thyridin-3-yl} amino)pyrimidin-2-yl]-4-methyl- piperidin-4-ol 139

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.17 (s, 1H), 9.14 (s, 1H), 8.76(s, 1H), 8.04 (d, 1H, J = 5.7 Hz), 7.74 (s, 1H), 6.47 (d, 1H, J = 5.7Hz), 4.96 (d, 1H, J = 49.6 Hz), 4.74 (t, 2H, J = 7.6 Hz), 4.50 (d, 1H, J= 13.3 Hz), 4.37-4.27 (m, 1H), 3.82-3.44 (m, 6H), 3.38 (s, 3H), 3.01 (s,3H), 3.05-2.86 (m, 1H), 1.95-1.69 (m, 2H), 1.48 (d, 3H, J = 6.1 Hz),1.32 (t, 6H, J = 7.2 Hz) N-{2-[(3S,4R)- 3-fluoro-4- methoxy-piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)-2,6-naph-thyridin-3-amine 140

558 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.17 (s, 1H), 9.14 (s, 1H), 8.76(s, 1H), 8.04 (d, 1H, J = 5.6 Hz), 7.74 (s, 1H), 6.47 (d, 1H, J = 5.6Hz), 4.96 (d, 1H, J = 50.0 Hz), 4.80-4.69 (m, 2H), 4.56-4.45 (m, 1H),4.32 (t, 1H, J = 6.3 Hz), 3.75 (dt, 3H, J = 16.2, 7.0 Hz), 3.57 (t, 3H,J = 6.7 Hz), 3.38 (s, 3H), 3.01 (s, 3H), 2.93 (q, 1H, J = 7.2 Hz),1.91-1.68 (m, 2H), 1.48 (d, 3H, J = 6.0 Hz), 1.32 (d, 6H, J = 6.7 Hz)N-{2-[(3R,4S)- 3-fluoro-4- methoxy- piperidin-1-yl] pyrimidin-4-yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)-2,6-naph- thyridin-3-amine 141

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.89 (s, 1H), 9.15 (s, 1H), 8.73(s, 1H), 8.47 (s, 1H), 7.50 (d, 1H, J = 8.0 Hz), 6.66 (d, 1H, J = 8.1Hz), 4.98 (s, 1H), 4.70 (t, 1H, J = 7.9 Hz), 4.56-4.29 (m, 2H),4.29-4.07 (m, 2H), 3.67 (t, 2H, J = 7.5 Hz), 3.59-3.40 (m, 4H), 3.00 (s,3H), 2.90 (q, 1H, J = 7.2 Hz), 1.81-1.59 (m, 2H), 1.47-1.39 (m, 3H),1.36-1.25 (m, 9H) M; Peak 1 (3R,4S)-3- fluoro-1-[5- ({8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino)-1,2,4- triazin-3-yl]-4- methyl-piperidin-4-ol 142

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.82 (s, 1H), 9.14 (s, 1H), 8.73(s, 1H), 8.48 (s, 1H), 7.49 (d, 1H, J = 8.0 Hz), 6.66 (d, 1H, J = 8.1Hz), 4.97 (s, 1H), 4.73- 4.65 (m, 1H), 4.52-4.42 (m, 2H), 4.25-4.17 (m,2H), 3.80-3.43 (m, 6H), 3.00 (s, 3H), 2.95-2.86 (m, 1H), 1.75 (s, 1H),1.64 (s, 1H), 1.47-1.39 (m, 3H), 1.35- 1.25 (m, 9H) M; Peak 2 (3S,4R)-3-fluoro-1-[5- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)-1,2,4-triazin-3-yl]-4- methyl- piperidin-4-ol 143

558 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.08 (s, 1H), 9.02 (s, 1H), 8.45(s, 1H), 8.03 (d, 1H, J = 5.6 Hz), 7.98 (s, 1H), 6.53 (d, 1H, J = 5.6Hz), 4.73-4.60 (m, 2H), 4.56 (t, 2H, J = 8.4 Hz), 4.21 (td, 2H, J = 6.7,6.2, 3.4 Hz), 3.59 (d, 2H, J = 7.4 Hz), 3.38 (s, 3H), 3.31-3.12 (m, 5H),3.01 (s, 3H), 1.97 (dd, 1H, J = 12.7, 4.0 Hz), 1.62 (q, 1H, J = 11.4Hz), 1.39 (d, 3H, J = 21.2 Hz), 1.33-1.26 (m, 6H) O; Peak 2 (in- ter-me- diate stage) N-{2-[(3S,4R)- 3-fluoro-4- methoxy-3- methyl-piperidin-1-yl] pyrimidin-4-yl}- 8-[3-(methane- sulfonylmethyl)azetidin-1-yl]-5- (propan-2-yl)- 2,7-naph- thyridin-3-amine 144

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.13 (s, 1H), 9.13 (s, 1H), 8.70(s, 1H), 8.03 (d, 1H, J = 5.7 Hz), 7.60 (s, 1H), 6.48 (d, 1H, J = 5.7Hz), 4.68 (d, 2H, J = 11.2 Hz), 4.49 (t, 2H, J = 7.7 Hz), 4.08 (t, 2H, J= 6.9 Hz), 3.71 (t, 1H, J = 6.7 Hz), 3.61 (d, 2H, J = 7.4 Hz), 3.39 (s,3H), 3.29-3.17 (m, 4H), 3.03 (s, 3H), 2.01-1.95 (m, 1H), 1.69- 1.63 (m,1H), 1.41 (d, 3H, J = 21.3 Hz), 1.31 (dd, 6H, J = 6.7, 3.9 Hz)N-{2-[(3S,4R)- 3-fluoro-4- methoxy-3- methyl- piperidin-1-yl]pyrimidin-4-yl}- 8-[3-(methane- sulfonylmethyl) azetidin-1-yl]-5-(propan-2-yl)- 2,6-naph- thyridin-3-amine 145

559 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.01 (s, 1H), 8.67(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.00 (d, 1H, J = 8.3 Hz), 6.43 (d,1H, J = 5.7 Hz), 6.37 (d, 1H, J = 8.3 Hz), 4.99 (d, 1H, J = 6.3 Hz),4.78 (dd, 1H, J = 14.1, 8.7 Hz), 4.68 (d, 1H, J = 13.3 Hz), 4.30 (t, 2H,J = 7.4 Hz), 4.17 (q, 2H, J = 6.9 Hz), 3.86 (t, 2H, J = 6.8 Hz),3.61-3.43 (m, 3H), 3.24 (dd, 1H, J = 14.0, 6.9 Hz), 3.13 (q, 3H, J = 7.3Hz), 1.75- 1.69 (m, 2H), 1.47-1.35 (m, 4H), 1.34-1.19 (m, 5H) NN; Peak 1(3S,4R)-1-{4- [(8-{3-[(ethane- sulfonyl)methyl] azetidin-1-yl}-5-ethoxyiso- quinolin-3-yl) amino] pyrimidin-2-yl}- 3-fluoro-3- methyl-piperidin-4-ol 146

559 1H NMR (400 MHz, MeOD-d₄) δ 9.10 (s, 1H), 8.62 (s, 1H), 7.46 (d, J =8.0 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.42 (d, J = 6.0 Hz, 1H),4.76-4.53 (m, 2H), 4.42 (t, J = 7.2 Hz, 3H), 4.01 (t, J = 6.4 Hz, 2H),3.85 (br d, J = 12.4 Hz, 1H), 3.73 (br s, 1H), 3.67-3.55 (m, 7H), 3.47-3.34 (m, 2H), 3.03 (s, 3H), 1.35 (d, J = 6.8 Hz, 6H) (3R,4R,5S)-5-fluoro-1-(4-((5- isopropyl-8-(3- ((methylsulfonyl) methyl)azetidin-1-yl)isoquinolin- 3-yl)amino) pyrimidin-2-yl)- 4-methoxy- piperidin-3-oland (3S,4S,5R)- 5-fluoro-1-(4- ((5-isopropyl-8- (3-((methyl-sulfonyl)methyl) azetidin-1-yl) isoquinolin-3-

yl)amino) pyrimidin-2-yl)- 4-methoxy- piperidin-3-ol 147

559 1H NMR (400 MHz, MeOD-d4) δ 9.10 (s, 1H), 8.61 (s, 1H), 7.97 (d, J =5.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 6.42(d, J = 5.6 Hz, 1H), 4.77-4.60 (m, 2H), 4.49-4.40 (m, 3H), 4.01 (t, J =8.0 Hz, 2H), 3.86-3.80 (m, 1H), 3.76-3.70 (m, 1H), 3.65-3.57 (m, 7H),3.44-3.36 (m, 2H), 3.02 (s, 3H), 1.35 (d, J = 6.8 Hz, 6H) (3S,4R,5R)-3-fluoro-1-(4-((5- isopropyl-8-(3- ((methylsulfonyl) methyl)azetidin-1-yl)isoquinolin- 3-yl)amino) pyrimidin-2-yl)- 5-methoxy- piperidin-4-oland (3R,4S,5S)- 3-fluoro-1-(4- ((5-isopropyl-8- (3-((methyl-sulfonyl)methyl) azetidin-1-yl) isoquinolin-3-yl)

amino) pyrimidin-2-yl)- 5-methoxy- piperidin-4-ol 148

559 1H NMR (400 MHz, MeOD-d4) δ 9.10 (s, 1H), 8.61 (s, 1H), 7.97 (d, J =5.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 6.42(d, J = 5.6 Hz, 1H), 4.77-4.60 (m, 2H), 4.49-4.40 (m, 3H), 4.01 (t, J =8.0 Hz, 2H), 3.86-3.80 (m, 1H), 3.76-3.70 (m, 1H), 3.65-3.57 (m, 7H),3.44-3.36 (m, 2H), 3.02 (s, 3H), 1.35 (d, J = 6.8 Hz, 6H) P; Peak 1(3R,4R,5S)-5- fluoro-1-[4- ({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]-4-methoxy- piperidin-3-ol or (3S,4S,5R)-5- fluoro-1-[4-({8- [3-(methane-sulfonylmethyl) azetidin-1-yl]-5- (propan-2-yl) isoquinolin-3-

yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol 149

559 1H NMR (400 MHz, MeOD-d4) δ 9.10 (s, 1H), 8.61 (s, 1H), 7.99 (d, J =5.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.42(d, J = 5.6 Hz, 1H), 4.64-4.59 (m, 1H), 4.54- 4.36 (m, 5H), 4.05-3.95(m, 2H), 3.74-3.57 (m, 4H), 3.50-3.47 (m, 1H), 3.43 (s, 3H), 3.42-3.35(m, 2H), 3.03 (s, 3H), 1.35 (dd, J = 3.2, 6.8 Hz, 6H) P; Peak 2(3S,4R,5R)-3- fluoro-1-[4- ({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]-5-methoxy- piperidin-4-ol or (3R,4S,5S)-3- fluoro-1-[4- ({8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin-

3-yl}amino) pyrimidin-2-yl]- 5-methoxy- piperidin-4-ol 150

559 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.43 (s, 1H), 9.11 (s, 1H), 8.62(s, 1H), 8.09 (d, 1H, J = 5.6 Hz), 6.54 (d, 1H, J = 5.6 Hz), 5.09- 4.82(m, 2H), 4.74-4.61 (m, 2H), 4.46 (d, 1H, J = 13.2 Hz), 4.07 (t, 1H, J =7.3 Hz), 3.73-3.42 (m, 5H), 3.37 (s, 3H), 3.00 (s, 3H), 2.97-2.88 (m,1H), 1.86-1.69 (m, 2H), 1.54 (d, 3H, J = 6.1 Hz), 1.37 (td, 6H, J = 6.6,3.8 Hz) 2-[(3S,4R)-3- fluoro-4- methoxy- piperidin-1-yl]- N-{4-[(2R,3S)-3-(methane- sulfonylmethyl)- 2-methyl- azetidin-1-yl]- 1-(propan-2-yl)pyrido[3,4-d] pyridazin-7-yl} pyrimidin-4- amine 151

560 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.03 (s, 1H), 9.07 (s, 1H), 8.59(s, 1H), 8.03 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.53 (d, 1H, J = 5.8 Hz), 4.89-4.81 (m, 1H), 4.66 (t,1H, J = 7.5 Hz), 4.55 (d, 1H, J = 13.6 Hz), 4.19 (q, 1H, J = 6.2 Hz),3.72-3.55 (m, 2H), 3.58-3.45 (m, 4H), 3.39-3.33 (m, 1H), 3.00 (s, 3H),2.89 (h, 1H, J = 7.2 Hz), 2.01-1.97 (m, 1H), 1.66-1.56 (m, 1H), 1.42 (d,3H, J = 6.1 Hz), 1.30 (dd, M; Peak 1 N-{2-[(4S)-4- amino-3,3- difluoro-piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methyl- azetidin-1-yl]- 5-(propan-2-yl) isoquinolin-3- amineor N-{2- [(4R)-4-amino- 3,3-difluoro- piperidin-1-yl]

6H, J = 6.8, 3.9 Hz) pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine152

560 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.99 (s, 1H), 9.06 (s, 1H), 8.61(s, 1H), 8.02 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.51 (d, 1H, J = 5.6 Hz), 4.68 (q, 2H, J = 9.3, 7.3Hz), 4.43-4.32 (m, 1H), 4.19 (t, 1H, J = 6.2 Hz), 3.79-3.56 (m, 2H),3.57-3.35 (m, 4H), 3.24-3.18 (m, 1H), 2.99 (s, 3H), 2.88 (q, 1H, J = 7.3Hz), 1.90- 1.84 (m, 1H), 1.61-1.51 (m, 1H), 1.42 (d, 3H, J = 6.0 Hz),1.30 (dd, 6H, J = 6.7, M; Peak 2 N-{2-[(4R)-4- amino-3,3- difluoro-piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine orN-{2- [(4S)-4-amino- 3,3-difluoro- piperidin-1-yl] pyrimidin-4-yl}-

1.9 Hz) 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- amine 153

561 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.04 (s, 1H), 8.58(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.40 (d, 1H, J = 8.0 Hz), 6.50 (d,1H, J = 5.7 Hz), 6.40 (d, 1H, J = 8.0 Hz), 5.53 (s, 1H), 4.77-4.65 (m,1H), 4.51-4.32 (m, 3H), 3.95 (t, 2H, J = 6.9 Hz), 3.64 (dd, 3H, J =40.3, 10.4 Hz), 3.53-3.42 (m, 1H), 3.22-3.17 (m, 1H), 3.00 (s, 3H),1.77-1.65 (m, 2H), 1.31-1.18 (m, 9H) F; Peak 2 (4S)-3,3-difluoro-1-[4-({8-[3- (methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan-2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]- 4-methyl- piperidin-4-olor (4R)-3,3- difluoro-1-[4- ({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan-

2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]- 4-methyl- piperidin-4-ol154

561 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.82 (s, 1H), 9.07 (s, 1H), 8.34(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 7.9 Hz), 6.58 (d,1H, J = 5.7 Hz), 6.38 (d, 1H, J = 7.9 Hz), 5.15-4.84 (m, 2H), 4.75 (dd,2H, J = 25.4, 14.9 Hz), 4.42 (t, 2H, J = 7.7 Hz), 4.00 (t, 2H, J = 6.9Hz), 3.60 (d, 2H, J = 7.3 Hz), 3.49 (dt, 1H, J = 11.2, 6.7 Hz),3.31-3.06 (m, 4H), 3.02 (s, 3H), 1.83-1.55 (m, 2H), 1.44-1.12 (m, 6H)NN; Peak 1 (3S,4R)-3- fluoro-1-(4- {[5-(1-fluoro- propan-2-yl)- 8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]isoquinolin- 3-yl]amino}pyrimidin-2-yl)- 3-methyl- piperidin-4-ol 155

561 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.07 (s, 1H), 8.54(s, 1H), 8.02 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.58 (d,1H, J = 5.7 Hz), 6.42 (d, 1H, J = 8.1 Hz), 5.68 (d, 1H, J = 6.0 Hz),5.10-5.00 (m, 1H), 4.92-4.78 (m, 1H), 4.66- 4.44 (m, 1H), 4.40 (t, 2H, J= 7.7 Hz), 3.97 (t, 2H, J = 6.9 Hz), 3.74-3.44 (m, 5H, J = 19.8, 7.1Hz), 3.31-3.08 (m, 3H), 3.02 (s, 3H), 1.41 (d, 3H, J = 21.5 Hz), 1.30(d, 6H, J = 6.7 Hz) C; Peak 1 (3S,4R,5R)-3,5- difluoro-1-[4- ({8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 3-methyl- piperidin-4-ol or (3R,4S,5S)-3,5-difluoro-1- [4-({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan-

2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]- 3-methyl- piperidin-4-ol156

561 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.91 (s, 1H), 9.04 (s, 1H), 8.54(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.40 (d, 1H, J = 8.0 Hz), 6.54 (d,1H, J = 5.7 Hz), 6.40 (d, 1H, J = 8.1 Hz), 5.85 (d, 1H, J = 5.3 Hz),4.89-4.62 (m, 1H), 4.37 (t, 2H, J = 7.7 Hz), 4.26-4.10 (m, 1H),4.10-4.01 (m, 1H), 4.03-3.72 (m, 5H), 3.57 (d, 2H, J = 7.4 Hz),3.54-3.42 (m, 1H), 3.29-3.19 (m, 1H), 3.00 (s, 3H), 1.45- 1.19 (m, 9H)I; Peak 2 (3R,4R,5R)-3,5- difluoro-1-[4- ({8-[3- (methanesulfonyl-methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino)pyrimidin-2-yl]- 3-methyl- piperidin-4-ol or (3S,4S,5S)- 3,5-difluoro-1-[4-({8-[3- (methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan-

2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]- 3-methyl- piperidin-4-ol157

561 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.84 (s, 1H), 9.07 (s, 1H), 8.56(s, 1H), 7.97 (d, 1H, J = 5.6 Hz), 7.31 (d, 1H, J = 15.6 Hz), 6.44 (d,1H, J = 5.6 Hz), 5.00 (d, 1H, J = 6.3 Hz), 4.71-4.65 (m, 1H), 4.63-4.57(m, 3H), 4.24-4.18 (m, 2H), 3.56 (d, 2H, J = 7.4 Hz), 3.52-3.46 (m, 2H),3.25-3.07 (m, 2H), 2.98 (s, 3H), 1.74-1.68 (m, 2H), 1.43-1.18 (m, 9H)NN; Peak 1 (3S,4R)-3- fluoro-1-[4-({7- fluoro-8-[3- (methanesulfonyl-methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino)pyrimidin-2-yl]- 3-methyl- piperidin-4-ol 158

561 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.04 (s, 1H), 8.54(s, 1H), 8.01 (d, 1H, J = 5.7 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.54 (d,1H, J = 5.7 Hz), 6.40 (d, 1H, J = 8.0 Hz), 4.46-4.24 (m, 3H), 4.06-4.00(m, 2H), 3.95 (t, 2H, J = 6.9 Hz), 3.75 (s, 2H), 3.57 (d, 2H, J = 7.4Hz), 3.49 (d, 1H, J = 6.6 Hz), 3.45 (s, 3H), 3.00 (s, 3H), 1.98-1.92 (m,1H), 1.78-1.72 (m, 1H), 1.27 (d, 6H, J = 6.7 Hz) PP; Peak 1N-{2-[(4S)-3,3- difluoro-4- methoxy- piperidin-1-yl] pyrimidin-4-yl}-8-[3- (methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan-2-yl)isoquinolin- 3-amine 159

561 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.04 (s, 1H), 8.54(s, 1H), 8.01 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 7.9 Hz), 6.54 (d,1H, J = 5.7 Hz), 6.40 (d, 1H, J = 8.0 Hz), 4.43-4.23 (m, 2H), 4.03 (s,2H), 3.95 (t, 2H, J = 6.8 Hz), 3.79-3.68 (m, 2H), 3.57 (d, 2H, J = 7.3Hz), 3.46-3.53 (m, 1H), 3.45 (s, 3H), 3.00 (s, 3H), 1.97- 1.91 (m, 1H),1.78-1.72 (m, 1H), 1.27 (d, 6H, J = 6.7 Hz) PP; Peak 2 N-{2-[(4R)-3,3-difluoro-4- methoxy- piperidin-1-yl] pyrimidin-4-yl}- 8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin-3-amine 160

561 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.12 (s, 1H), 9.02 (s, 1H), 8.47(s, 1H), 8.08 (d, 1H, J = 5.6 Hz), 7.98 (s, 1H), 6.58 (d, 1H, J = 5.7Hz), 5.97 (t, 1H), 4.65-4.51 (m, 3H), 4.44 (d, 1H, J = 12.5 Hz), 4.22(td, 2H, J = 6.6, 3.3 Hz), 3.58 (d, 2H, J = 7.4 Hz), 3.31-3.25 (m, 2H),3.11 (q, 3H, J = 7.4 Hz), 3.01 (t, 3H, J = 9.9 Hz), 2.80-2.64 (m, 2H),1.38-1.14 (m, 9H) I; Peak 2 N-{2-[(3R)-3- (difluoromethyl)piperazin-1-yl] pyrimidin-4-yl}- 8-{3-[(ethane- sulfonyl)methyl]azetidin-1-yl}-5- (propan-2-yl)- 2,7-naph- thyridin-3-amine orN-{2-[(3S)-3- (difluoromethyl) piperazin-1-yl] pyrimidin-4-yl}-8-{3-[(ethane- sulfonyl)methyl]

azetidin-1-yl}-5- (propan-2-yl)- 2,7-naph- thyridin-3-amine 161

561 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.19 (s, 1H), 9.14 (s, 1H), 8.76(s, 1H), 8.04 (d, 1H, J = 5.7 Hz), 7.74 (s, 1H), 6.47 (d, 1H, J = 5.7Hz), 4.96 (dd, 1H, J = 49.5, 4.7 Hz), 4.74 (dd, 2H, J = 9.2, 6.0 Hz),4.50 (d, 1H, J = 13.2 Hz), 4.32 (p, 1H, J = 6.1 Hz), 3.83-3.58 (m, 3H),3.62-3.38 (m, 3H), 3.33-3.23 (m, 1H), 3.01 (s, 3H), 2.92 (p, 1H, J = 7.3Hz), 1.90-1.70 (m, 2H), 1.48 (d, 3H, J = 6.0 Hz), 1.32 (d, G; Peak 1N-{2-[(3S,4R)- 3-fluoro-4- (²H3)methoxy- piperidin-1-yl]pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)-2,6-naph- thyridin-3-amine orN-{2-[(3R,4S)- 3-fluoro-4- (²H3)methoxy-

6H, J = 6.6 Hz) piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3- (methane-sulrfonylmethyl)- 2-methylazetidin- 1-yl]-5-(propan- 2-yl)-2,6-naph-thyridin-3-amine 162

561 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.18 (s, 1H), 9.14 (s, 1H), 8.76(s, 1H), 8.04 (d, 1H, J = 5.6 Hz), 7.73 (s, 1H), 6.47 (d, 1H, J = 5.7Hz), 4.96 (d, 1H, J = 50.2 Hz), 4.74 (t, 1H, J = 7.5 Hz), 4.50 (d, 1H, J= 13.6 Hz), 4.32 (p, 1H, J = 6.1 Hz), 3.83-3.71 (m, 3H), 3.75-3.43 (m,3H), 3.33-3.23 (m, 1H), 3.01 (s, 3H), 2.93 (q, 1H, J = 7.2 Hz),1.90-1.69 (m, 2H), 1.48 (d, 3H, J = 6.0 Hz), 1.39-1.27 (m, 6H) G; Peak 2N-{2-[(3R,4S)- 3-fluoro-4- (²H3)methoxy- piperidin-1-yl]pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin- 1-yl]-5-(propan- 2-yl)-2,6-naph- thyridin-3-amine orN-{2- [(3S,4R)-3- fluoro-4-

(²H3)methoxy- piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)-2,6-naph- thyridin-3-amine 163

562 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.03 (s, 1H), 8.49 (s,1H), 8.08-7.93 (m, 2H), 6.48 (d, J = 5.6 Hz, 1H), 5.00 (d, J = 6.4 Hz,1H), 4.75-4.51 (m, 6H), 3.82 (s, 2H), 3.62-3.46 (m, 1H), 3.19-3.04 (m,2H), 2.76 (s, 3H), 1.72 (br.s, 2H), 1.49-1.16 (m, 11H). NN; Peak 1(3S,4R)-3- fluoro-1-(4- {[5-(1-fluoro- propan-2-yl)- 8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-2,7-naph- thyridin-3-yl]amino}pyrimidin- 2-yl)-3- methyl- piperidin-4-ol 164

564 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.06 (s, 1H), 9.07 (s, 1H), 8.59(s, 1H), 8.03 (d, 1H, J = 5.8 Hz), 7.44 (d, 1H, J = 8.0 Hz), 6.58 (d,2H, J = 8.1 Hz), 4.81 (d, 1H, J = 13.7 Hz), 4.66 (t, 1H, J = 7.6 Hz),4.60-4.54 (m, 1H), 4.20 (t, 1H, J = 6.5 Hz), 3.72-3.43 (m, 8H),3.27-3.10 (m, 1H), 2.99 (s, 3H), 2.93- 2.84 (m, 1H), 1.98-1.92 (m, 1H),1.68-1.62 (m, 1H), 1.42 (d, 3H, J = 6.0 Hz), 1.32 (d, 6H, J = 6.7 Hz) B;Peak 1 (3S,4S)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 4-methoxy- piperidine-3- carbonitrile or (3R,4R)-1-[4-({8-[(2R,3S)-3- (methanesulfonyl-

methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidine-3- carbonitrile 165

564 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.04 (s, 1H), 9.07 (s, 1H), 8.58(s, 1H), 8.03 (d, 1H, J = 5.7 Hz), 7.44 (d, 1H, J = 8.1 Hz), 6.62-6.42(m, 2H), 4.92-4.44 (m, 3H), 4.22-4.14 (m, 1H), 3.76- 3.40 (m, 8H),3.31-3.13 (m, 1H), 2.99 (s, 3H), 2.90-2.84 (m, 1H), 1.98-1.92 (m, 1H),1.76-1.56 (m, 1H), 1.42 (d, 3H, J = 6.0 Hz), 1.32 (dd, 6H, J = 6.8, 2.8Hz) B; Peak 2 (3R,4R)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl- 4-methoxy- piperidine-3- carbonitrile or (3S,4S)-1-[4-({8-[(2R,3S)-3- (methanesulfonyl-

methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidine-3- carbonitrile 166

564 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.05 (s, 1H), 9.06 (s, 1H), 8.54(s, 1H), 8.04 (d, 1H, J = 5.8 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,2H, J = 7.8 Hz), 4.66 (t, 1H, J = 7.4 Hz), 4.50-4.39 (m, 1H), 4.32-4.07(m, 2H), 3.77-3.48 (m, 8H), 3.38- 3.21 (m, 3H), 2.99 (s, 3H), 2.93-2.84(m, 1H), 2.15- 2.05 (m, 1H), 1.52-1.38 (m, 4H), 1.31 (dd, 6H, J = 8.9,6.8 Hz) K; Peak 2 (3S,4R)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidine-3- carbonitrile or(3R,4S)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-

methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidine-3- carbonitrile 167

567 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.84 (s, 1H), 9.03 (s, 1H), 8.66(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.40 (d, 1H, J = 8.0 Hz), 6.46- 6.35(m, 2H), 4.43-4.26 (m, 4H), 3.94 (t, 2H, J = 6.9 Hz), 3.68 (s, 2H), 3.57(d, 4H, J = 7.4 Hz), 3.51-3.32 (m, 4H), 3.25 (d, 1H, J = 7.3 Hz), 3.00(s, 3H), 1.92-1.81 (m, 2H), 1.59-1.45 (m, 2H), 1.28 (d, 6H, J = 6.7 Hz)N-(2-{1,4- dioxa-9- azaspiro[5,5] undecan-9-yl} pyrimidin-4- yl)-8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin-3-amine 168

568 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.91 (s, 1H), 9.05 (s, 1H), 8.69(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.43 (d, 1H, J = 5.7 Hz), 4.66 (t, 1H, J = 7.5 Hz),4.38-4.27 (m, 2H), 4.19 (t, 1H, J = 6.2 Hz), 3.69-3.37 (m, 9H), 3.00 (s,3H), 2.89 (q, 1H, J = 7.1 Hz), 2.71 (t, 2H, J = 5.8 Hz), 1.95-1.89 (m,2H), 1.52-1.39 (m, 5H), 1.30 (d, 6H, J = 6.7 Hz) N-{2-[4-(2-aminoethoxy) piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- amine 169

568 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.06 (s, 1H), 8.70(s, 1H), 8.25 (s, 1H), 8.01 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0Hz), 6.57 (d, 1H, J = 8.2 Hz), 6.45 (d, 1H, J = 5.6 Hz), 4.67 (t, 1H, J= 7.5 Hz), 4.42 (d, 2H, J = 13.0 Hz), 4.19 (q, 1H, J = 6.4 Hz),3.68-3.22 (m, 11H), 3.01 (s, 3H), 2.96-2.85 (m, 3H), 1.85 (d, 2H, J =13.6 Hz), 1.60-1.52 (m, 2H), 1.43 (d, 3H, J = 6.1 Hz), 1.31 (d, 6H, J =6.8 Hz) N-{2-[4- (aminomethyl)- 4-methoxy- piperidin-1-yl]pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine 170

569 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.86 (s, 1H), 9.06 (s, 1H), 8.60(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.47 (d,1H, J = 5.6 Hz), 6.41 (d, 1H, J = 8.0 Hz), 4.82-4.64 (m, 2H), 4.40 (t,2H, J = 7.8 Hz), 3.98 (t, 2H, J = 6.9 Hz), 3.68-3.59 (m, 2H), 3.51 (s,2H), 3.38-2.98 (m, 3H), 2.79-2.70 (m, 2H), 1.74 (s, 2H), 1.55-1.20 (m,9H), 1.03 (t, 4H, J = 7.2 Hz) (3S,4R)-1-{4- [(8-{3-[(cyclo-propanesulfonyl) methyl]azetidin- 1-yl}-5- (propan-2-yl) isoquinolin-3-yl)amino] pyrimidin-2-yl}- 3-fluoro-3- methyl- piperidin-4-ol 171

569 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.90 (s, 1H), 9.05 (s, 1H), 8.69(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.43 (d, 1H, J = 5.7 Hz), 4.66 (t, 1H, J = 7.5 Hz),4.64-4.55 (m, 1H), 4.40-4.29 (m, 2H), 4.20 (t, 1H, J = 6.3 Hz),3.71-3.33 (m, 11H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.1 Hz), 1.99- 1.88(m, 2H), 1.57-1.39 (m, 5H), 1.30 (d, 6H, J = 6.7 Hz) 2-({1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]piperidin-4-yl} oxy)ethan-1-ol 172

569 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.87 (s, 1H), 9.05 (s, 1H), 8.64(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.46 (d, 1H, J = 5.6 Hz), 4.66 (t, 1H, J = 7.5 Hz),4.60-4.46 (m, 3H), 4.20 (t, 1H, J = 6.3 Hz), 3.55 (tdd, 7H, J = 25.6,12.6, 6.1 Hz), 3.32 (s, 2H), 3.27-3.03 (m, 2H), 3.00 (s, 3H), 2.89 (q,1H, J = 7.2 Hz), 2.14- 2.04 (m, 1H), 1.64-1.58 (m, L; Peak 2[(3R,4S)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 4-methoxy- piperidin-3-yl] methanol or [(3S,4R)-1-[4-({8-[(2R,3S)-3-

1H), 1.43 (d, 3H, J = 6.0 Hz), 1.31 (t, 7H, J = 7.0 Hz)(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-yl]methanol 173

569 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.86 (s, 1H), 9.05 (s, 1H), 8.63(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.46 (d, 1H, J = 5.6 Hz), 4.66 (t, 1H, J = 7.4 Hz),4.59-4.40 (m, 3H), 4.20 (t, 1H, J = 6.2 Hz), 3.72-3.35 (m, 7H), 3.31 (s,3H), 3.11-3.05 (m, 1H), 3.00 (s, 3H), 2.93-2.85 (m, 1H), 2.10-2.04 (m,1H), 1.64-1.58 (m, 1H), 1.43 (d, 3H, J = 6.0 Hz), 1.31 (dd, 7H, J = 6.7,F; Peak 1 [(3R,4R)-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 4-methoxy- piperidin-3-yl] methanol or [(3S,4S)-1-[4-({8-[(2R,3S)-3- (methanesulfonyl-

4.1 Hz) methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-yl] methanol 174

569 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.87 (s, 1H), 9.05 (s, 1H), 8.66(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.60- 6.50(m, 1H), 6.45 (d, 1H, J = 5.7 Hz), 4.66 (t, 1H, J = 7.4 Hz), 4.42 (t,1H, J = 5.3 Hz), 4.27-4.17 (m, 3H), 3.69-3.40 (m, 7H), 3.33 (s, 3H),3.00 (s, 3H), 2.93-2.85 (m, 1H), 1.90-1.84 (m, 2H), 1.61-1.55 (m, 1H),1.43 (d, 3H, J = 6.0 Hz), 1.34-1.21 (m, 6H) F; Peak 2 [(3S,4R)-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methoxy-piperidin-3-yl] methanol or [(3R,4S)-1-[4- ({8-[(2R,3S)-3-(methanesulfonyl-

methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-yl] methanol 175

569 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.88 (s, 1H), 9.04 (s, 1H), 8.71(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.55 (d,1H, J = 8.0 Hz), 6.40 (d, 1H, J = 5.7 Hz), 4.71-4.54 (m, 2H), 4.46-4.36(m, 2H), 4.19 (t, 1H, J = 6.2 Hz), 3.69-3.43 (m, 4H), 3.40 (d, 2H, J =5.5 Hz), 3.31-3.24 (m, 2H), 3.22 (s, 3H), 2.99 (s, 3H), 2.88 (q, 1H, J =6.9 Hz), 1.79-1.68 (m, 2H), 1.55-1.49 (m, 2H), 1.42 (d, 3H, J = 6.1 Hz),1.29 (d, 6H, J = 6.7 Hz) {1-[4-({8- [(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-4-yl} methanol 176

569 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.87 (s, 1H), 9.05 (s, 1H), 8.69(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.41 (d, 1H, J = 5.6 Hz), 4.71-4.60 (m, 2H), 4.25-4.15(m, 1H), 4.01-3.95 (m, 2H), 3.82- 3.76 (m, 2H), 3.76-3.42 (m, 6H), 3.37(s, 3H), 3.10 (q, 2H, J = 7.4 Hz), 2.89 (q, 1H, J = 7.3 Hz), 1.94-1.57(m, 2H), 1.43 (d, 3H, J = 6.0 Hz), 1.34-1.18 (m, 9H) JJ Peak 1(3S,4R)-1-[4- ({8-[(2R,3S)-3- [(ethanesulfonyl) methyl]-2-methylazetidin- 1-yl]-5- (propan-2-yl) isoquinolin-3- yl}amino)pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol, or (3R,4S)-1- [4-({8-[(2R,3S)-3- [(ethanesulfonyl)

methyl]-2- methylazetidin- 1-yl]-5- (propan-2-yl) isoquinolin-3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol 177

569 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.90 (s, 1H), 9.05 (s, 1H), 8.66(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.45 (d, 1H, J = 5.7 Hz), 5.11 (d, 1H, J = 4.8 Hz),4.66 (t, 1H, J = 7.5 Hz), 4.39 (dt, 2H, J = 17.0, 8.5 Hz), 4.19 (q, 1H,J = 6.2 Hz), 3.64 (t, 1H, J = 7.1 Hz), 3.58-3.42 (m, 3H), 3.37 (s, 3H),3.30-3.16 (m, 2H), 3.10 (q, 3H), 2.89 (q, 1H, J = 7.2 Hz), 2.11-2.01 (m,1H), 1.43 (d, 3H, J = 6.0 Hz), 1.40- LL, Peak 1 (3S,4S)-1-[4-({8-[(2R,3S)-3- [(ethanesulfonyl) methyl]-2- methylazetidin- 1-yl]-5-(propan-2-yl) isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methoxy-piperidin-3-ol or (3R,4R)- 1-(4-((8- ((2R,3S)-3- ((ethylsulfonyl)

1.34 (m, 1H), 1.32-1.11 (m, 9H) methyl)-2- methylazetidin- 1-yl)-5-iso-propyliso- quinolin-3- yl)amino) pyrimidin-2-yl)- 4-methoxy-piperidin-3-ol 178

570 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.06 (s, 1H), 9.02 (s, 1H), 8.57(s, 1H), 8.02 (d, 1H, J = 5.6 Hz), 7.99 (s, 1H), 6.44 (d, 1H, J = 5.6Hz), 4.85 (t, 1H, J = 8.1 Hz), 4.65 (d, 1H, J = 5.0 Hz), 4.55 (t, 1H, J= 6.3 Hz), 4.10-3.87 (m, 3H), 3.81-3.62 (m, 4H), 3.55-3.39 (m, 6H), 3.07(t, 2H, J = 7.4 Hz), 2.88 (d, 1H, J = 7.1 Hz), 1.91-1.82 (m, 1H),1.65-1.59 (m, 1H), 1.49 (d, 3H, J = 6.1 Hz), 1.36-1.16 (m, 9H) JJ, Peak1 (3S,4R)-1-[4- ({8-[(2R,3S)-3- [(ethanesulfonyl) methyl]-2-methylazetidin- 1-yl]-5-(propan- 2-yl)-2,7-naph- thyridin-3-yl} amino)pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol 179

570 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.09 (s, 1H), 9.03 (s, 1H), 8.54(s, 1H), 8.03 (d, 1H, J = 5.6 Hz), 7.99 (s, 1H), 6.48 (d, 1H, J = 5.7Hz), 5.10 (d, 1H, J = 4.9 Hz), 4.85 (t, 1H, J = 8.0 Hz), 4.55 (t, 1H, J= 6.2 Hz), 4.42-4.26 (m, 2H), 3.97 (t, 1H, J = 7.3 Hz), 3.51 (d, 2H, J =7.4 Hz), 3.38 (s, 3H), 3.24 (d, 5H, J = 9.1 Hz), 3.08 (q, 2H, J = 7.5Hz), 2.95-2.84 (m, 1H), 2.10-2.00 (m, 1H), 1.49 (d, 3H, J = 6.1 Hz),1.44- 1.32 (m, 1H), 1.31 (t, 6H, J = 7.6 Hz), 1.22 (t, 3H, J = 7.4 Hz)LL, Peak 1 (3S,4S)-1-[4- ({8-[(2R,3S)-3- [(ethanesulfonyl) methyl]-2-methylazetidin- 1-yl]-5-(propan- 2-yl)-2,7-naph- thyridin-3-yl} amino)pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol 180

571 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.91 (s, 1H), 9.06 (s, 1H), 8.58(s, 1H), 8.02 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.54 (d,1H, J = 5.8 Hz), 6.42 (d, 1H, J = 8.0 Hz), 4.64-4.32 (m, 4H), 4.19 (d,1H, J = 14.0 Hz), 4.07-3.93 (m, 6H), 3.93-3.79 (m, 1H), 3.70 (d, 1H, J =9.0 Hz), 3.59 (d, 2H, J = 7.4 Hz), 3.48 (p, 1H, J = 6.7, 6.1 Hz), 3.28-3.22 (m, 1H, J = 6.9 Hz), 3.02 (s, 3H), 2.00-1.82 (m, 1H), 1.72-1.61 (m,1H), 1.39-1.21 (m, 6H) M; Peak 1 N-{2-[(6R)-6- fluoro-1,4- dioxa-8-azaspiro[4.5] decan-8-yl] pyrimidin-4-yl}- 8-[3- (methanesulfonyl-methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine or N-{2-[(6S)-6- fluoro-1,4-dioxa- 8-azaspiro[4.5] decan-8-yl]pyrimidin-4-yl}-

8-[3- (methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan-2-yl)isoquinolin- 3-amine 181

571 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.91 (s, 1H), 9.06 (s, 1H), 8.58(s, 1H), 8.02 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.54 (d,1H, J = 5.7 Hz), 6.42 (d, 1H, J = 8.0 Hz), 4.63-4.30 (m, 4H), 4.24-4.13(m, 1H), 4.07-3.79 (m, 7H), 3.69 (t, 1H, J = 9.9 Hz), 3.59 (d, 2H, J =7.4 Hz), 3.55-3.40 (m, 1H), 3.28 (d, 1H, J = 8.1 Hz), 3.02 (s, 3H),1.94-1.88 (m, 1H), 1.72-1.61 (m, 1H), 1.39-1.21 (m, 6H) M; Peak 2N-{2-[(6R)-6- fluoro-1,4- dioxa-8- azaspiro[4.5] decan-8-yl]pyrimidin-4-yl}- 8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine or N- {2-[(6S)-6- fluoro-1,4-dioxa-8- azaspiro[4.5] decan-8-yl]

pyrimidin-4-yl}- 8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine 182

571 1H-NMR (300 MHz, 6d- DMSO) δ ppm (s, 1H), 9.05 (s, 1H), 8.58 (s,1H), 7.99 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.49 (d, 1H, J= 5.6 Hz), 6.41 (d, 1H, J = 8.1 Hz), 5.14 (d, 1H, J = 5.3 Hz), 4.76 (d,1H, J = 48.7 Hz), 4.39 (t, 2H, J = 7.6 Hz), 4.33-4.17 (m, 1H), 4.12-3.89(m, 3H), 3.66-3.39 (m, 6H), 3.31-3.21 (m, 1H), 3.12 (q, 2H, J = 7.4 Hz),1.36- 1.16 (m, 9H), 1.03-0.84 (m, 6H) J; Peak 2 (4S,5R)-1-{4- [(8-{3-[(ethanesulfonyl) methyl]azetidin- 1-yl}-5-(propan- 2-yl)isoquinolin-3-yl)amino] pyrimidin-2-yl}- 5-fluoro-3,3- dimethyl- piperidin-4-ol or(4R,5S)-1- {4-[(8-{3- [(ethanesulfonyl) methyl]azetidin-1-yl}-5-(propan- 2-yl)isoquinolin- 3-yl)amino]

pyrimidin-2-yl}- 5-fluoro-3,3- dimethyl- piperidin-4-ol 183

571 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.06 (s, 1H), 8.60(s, 1H), 7.99 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.47 (d, 1H, J = 5.6 Hz), 5.13 (d, 1H, J = 5.4 Hz),4.92-4.55 (m, 2H), 4.31-4.15 (m, 2H), 3.97 (dd, 1H, J = 23.3, 13.5 Hz),3.84 (d, 1H, J = 12.9 Hz), 3.64 (t, 1H, J = 7.3 Hz), 3.54 (p, 3H, J =6.8 Hz), 3.47-3.37 (m, 2H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.2 Hz), 1.43(d, 3H, J = 6.0 Hz), 1.30 (t, 6H, J = 7.1 Hz), 0.98-0.90 (m, 6H) L; Peak2 (4S,5R)-5- fluoro-1-[4- ({8-[(2S,3R)-3- (methanesulfonyl- methyl)-2-methylazetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino)pyrimidin-2-yl]- 3,3-dimethyl- piperidin-4-ol or (4R,5S)-5- fluoro-1-[4-({8-[(2S,3R)-3- (methanesulfonyl- methyl)-2- methylazetidin-

1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]-3,3-dimethyl- piperidin-4-ol 184

571 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.03 (s, 1H), 9.07 (s, 1H), 8.60(s, 1H), 7.99 (d, 1H, J = 5.8 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.50 (d, 1H, J = 5.8 Hz), 5.00 (s, 1H), 4.71-4.54 (m,3H), 4.20 (p, 1H, J = 6.1 Hz), 3.66 (dt, 2H, J = 20.7, 7.2 Hz),3.61-3.44 (m, 3H), 3.31-3.19 (m, 2H), 2.99 (s, 3H), 2.96-2.84 (m, 1H),1.86 (dt, 1H, J = 16.6, 7.8 Hz), 1.80-1.60 D; Peak 2 (3R,4S)-3-ethyl-3-fluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl] piperidin-4-ol or (3S,4R)-3-ethyl- 3-fluoro-1-[4-({8-[(2R,3S)-3- (methanesulfonyl-

(m, 3H), 1.42 (d, 3H, J = 6.1 Hz), 1.34-1.26 (m, 6H), 0.93 (t, 3H, J =7.5 Hz) methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl] piperidin-4-ol 185

571 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.92 (s, 1H), 9.06 (s, 1H), 8.60(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 7.9 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.48 (d, 1H, J = 5.7 Hz), 4.73-4.64 (m, 3H), 4.25-4.15(m, 1H), 3.59 (dt, 4H, J = 29.1, 7.5 Hz), 3.39 (s, 3H), 3.30-3.16 (m,3H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.4, 6.7 Hz), 2.03-1.93 (m, 1H),1.68-1.62 (m, 1H), 1.47-1.26 (m, 12H) NN; Peak 1 N-{2-[(3S,4R)-3-fluoro-4- methoxy-3- methylpiperidin- 1-yl]pyrimidin- 4-yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- amine 186

571 1H NMR (400 MHz, DMSO- d6) δ 9.94 (s, 1H), 9.08 (s, 1H), 8.68 (s,1H), 8.03 (d, 1H, J = 5.5 Hz), 7.45 (d, 1H, J = 8.0 Hz), 6.59 (d, 1H, J= 8.0 Hz), 6.50 (d, 1H, J = 5.6 Hz), 4.85 (s, 1H), 4.68 (t, 1H, J = 7.5Hz), 4.57-4.39 (m, 1H), 4.32-4.14 (m, 2H), 3.67 (t, 2H, J = 7.1 Hz),3.53 (q, 4H, J = 6.7 Hz), 3.12 (q, 2H, J = 7.4 Hz), 2.91 (q, 1H, J = 7.1Hz), 1.66 (m, 2H), 1.46 (d, 3H, J = 6.0 Hz), 1.39-1.20 (m, 12H). OO;Peak 1 (3S,4R)-1-[4- ({8-[(2R,3S)-3- [(ethanesulfonyl) methyl]-2-methylazetidin- 1-yl]-5- (propan-2-yl) isoquinolin-3- yl}amino)pyrimidin-2-yl]- 3-fluoro-4- methyl- piperidin-4-ol 187

571 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.09 (s, 1H), 8.72- 8.61(m, 1H), 8.04 (d, 1H, J = 5.6 Hz), 7.45 (d, 1H, J = 7.9 Hz), 6.59 (d,1H, J = 8.1 Hz), 6.50 (d, 1H, J = 5.6 Hz), 4.85 (s, 1H), 4.68 (t, 1H, J= 7.5 Hz), 4.55-4.37 (m, 1H), 4.23 (dd, 2H, J = 12.3, 6.0 Hz), 3.67 (t,2H, J = 7.1 Hz), 3.54 (t, 4H, J = 7.1 Hz), 3.12 (q, 2H, J = 7.4 Hz),1.66 (m, 2H), 1.46 (d, 3H, J = 6.1 Hz), 1.37-1.20 (m, 12H). OO; Peak 2(3R,4S)-1-[4- ({8-[(2R,3S)-3- [(ethanesulfonyl) methyl]-2-methylazetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino)pyrimidin-2-yl]- 3-fluoro-4- methyl- piperidin-4-ol 188

572 ¹H NMR (400 MHz, 6d- DMSO) δ ppm 10.08 (s, 1H), 9.02 (s, 1H), 8.48(s, 1H), 8.03 (d, 1H, J = 5.6 Hz), 7.99 (s, 1H), 6.50 (d, 1H, J = 5.6Hz), 5.03 (d, 1H, J = 6.4 Hz), 4.84-4.63 (m, 2H), 4.56 (t, 2H, J = 8.4Hz), 4.22 (td, 2H, J = 7.3, 6.9, 3.4 Hz), 3.70- 3.45 (m, 3H), 3.29-3.00(m, 3H), 1.74 (d, 2H, J = 9.4 Hz), 1.45-1.28 (m, 9H), 1.26 (d, 6H, J =6.8 Hz) NN; Peak 1 (3S,4R)-3- fluoro-3- methyl-1-(4- {[5-(propan-2-yl)-8-3- [(propane-2- sulfonyl) methyl]azetidin- 1-yl}-2,7-naph-thyridin-3-yl] amino} pyrimidin-2-yl) piperidin-4-ol 189

572 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.10 (s, 1H), 9.05 (s, 1H), 8.50(s, 1H), 8.09-7.98 (m, 2H), 6.51 (d, 1H, J = 5.6 Hz), 5.04 (d, 1H, J =6.4 Hz), 4.86 (t, 1H, J = 8.0 Hz), 4.81-4.49 (m, 3H), 3.98 (t, 1H, J =7.3 Hz), 3.67-3.47 (m, 3H), 3.34 (d, 1H, J = 13.8 Hz), 3.18 (s, 1H),3.09 (q, 3H, J = 7.4 Hz), 2.91 (p, 1H, J = 7.2 Hz), 1.80-1.67 (m, 2H),1.50 (d, 3H, J = 6.1 Hz), 1.43-1.29 (m, 9H), 1.23 (t, 3H, J = 7.4 Hz) D;Peak 2 (3S,4R)-1-[4- ({8-[(2S,3R)-3- [(ethanesulfonyl) methyl]-2-methylazetidin- 1-yl]-5-propan- 2-yl)-2,7- naphthyridin-3- yl}amino)pyrimidin-2-yl]- 3-fluoro-3- methyl- piperidin-4-ol 190

572 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.15 (s, 1H), 9.04 (s, 1H), 8.55(s, 1H), 8.10-7.98 (m, 2H), 6.51 (d, 1H, J = 5.7 Hz), 4.91-4.80 (m, 2H),4.55 (q, 1H, J = 6.2 Hz), 4.50-4.11 (m, 3H), 3.98 (t, 1H, J = 7.3 Hz),3.62 (td, 1H, J = 12.6, 11.4, 5.0 Hz), 3.52 (d, 2H, J = 7.5 Hz), 3.463.38 (m, 1H), 3.09 (q, 2H, J = 7.4 Hz), 2.89 (q, 1H, J = 7.2 Hz),1.73-1.67 (m, 1H), 1.59-1.53 (m, 1H), 1.50 (d, 3H, J = 6.1 Hz), 1.32 (t,6H, J = 7.4 Hz), 1.29-1.17 (m, 6H) OO; Peak 1 (3S,4R)-1-[4-({8-[(2R,3S)-3- [(ethanesulfonyl) methyl]-2- methylazetidin-1-yl]-5-(propan- 2-yl)-2,7-naph- thyridin-3- yl}amino) pyrimidin-2-yl]-3-fluoro-4- methyl- piperidin-4-ol 191

572 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.15 (s, 1H), 9.04 (s, 1H), 8.55(s, 1H), 8.06 (d, 1H, J = 5.6 Hz), 8.01 (s, 1H), 6.51 (d, 1H, J = 5.7Hz), 4.92-4.80 (m, 2H), 4.56 (p, 1H, J = 6.1 Hz), 4.43 (q, 1H, J = 7.1,5.4 Hz), 4.32-4.12 (m, 2H), 3.98 (t, 1H, J = 7.3 Hz), 3.62 (ddd, 1H, J =13.5, 9.7, 5.1 Hz), 3.52 (d, 3H, J = 7.6 Hz), 3.35-3.27 (m, 1H), 3.09(q, 2H, J = 7.4 Hz), 2.89 (q, 1H, J = 7.2 Hz), 1.73-1.67 (m, 1H),1.60-1.54 (m, 1H), 1.50 (d, 3H, J = 6.1 Hz), 1.36- 1.17 (m, 12H) OO;Peak 2 (3R,4S)-1-[4- ({8-[(2R,3S)-3- [(ethanesulfonyl) methyl]-2-methylazetidin- 1-yl]-5-propan- 2-yl)-2,7-naph- thyridin-3- yl}amino)pyrimidin-2-yl]- 3-fluoro-4- methyl- piperidin-4-ol 192

572 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.86 (s, 1H), 9.03 (s, 1H), 8.39(s, 1H), 7.96 (d, 1H, J = 5.6 Hz), 7.46 (t, 1H, J = 7.9 Hz), 7.03 (d,1H, J = 8.1 Hz), 6.39 (d, 1H, J = 5.6 Hz), 6.33 (d, 1H, J = EE, Peak 2(4S,5R)-1-(4- {[8-(3-{[2- (dimethylamino) ethanesulfonyl] methyl}azetidin-1-yl) isoquinolin-3-

7.7 Hz), 5.12 (d, 1H, J = 5.4 Hz), 4.74 (d, 1H, J = 49.7 Hz), 4.44 (t,2H, J = 7.8 Hz), 4.27-4.21 (m, 1H), 4.01 (t, 2H, J = 6.9 Hz), 3.89 (d,1H, J = 11.5 Hz), 3.80 (d, 1H, J = 14.4 Hz), 3.63 (d, 2H, J = 7.4 Hz),3.54-3.35 (m, 5H), 2.64 (t, 2H, J = 6.9 Hz), 2.17 (s, 6H), 0.95 (d,yl]amino} pyrimidin-2-yl)- 5-fluoro-3,3- dimethyl- piperidin-4-ol or(4R,5S)-1-(4- {[8-(3-{[2- (dimethylamino) ethanesulfonyl] methyl} 6H, J= 5.9 Hz) azetidin-1-yl) isoquinolin-3- yl]amino} pyrimidin-2-yl)-5-fluoro-3,3- dimethyl- piperidin-4-ol 193

572 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.91 (s, 1H), 9.07 (s, 1H), 8.63(s, 1H), 8.01 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.49 (d,1H, J = 5.8 Hz), 6.43 (d, 1H, J = 8.0 Hz), 4.95 (d, 1H, J = 49.7 Hz),4.74 (s, 1H), 4.57-4.31 (m, 3H), 4.08 (t, 1H, J = 7.5 Hz), 3.97 (t, 1H,J = 7.3 Hz), 3.68-3.39 (m, 5H), 3.37 (s, 3H), 3.33-3.19 (m, 3H), 3.06(s, 3H), 3.01 (d, 2H, J = 4.8 Hz), 1.84- K; Peak 1 (Pre- cusor stage)8-{3-[(1R)-2- amino-1- methanesulfonyl- ethyl]azetidin-1- yl}-N-{2-[(3S,4R)-3- fluoro-4- methoxy- piperidin-1-yl] pyrimidin-4-yl}-5-(propan-2- yl)isoquinolin- 3-amine or 8- {3-[(1S)-2-

1.73 (m, 2H), 1.31 (dd, 6H, J = 6.8, 2.8 Hz) amino-1- methanesulfonyl-ethyl]azetidin-1- yl}-N-{2- [(3S,4R)-3- fluoro-4- methoxy-piperidin-1-yl] pyrimidin-4-yl}- 5-(propan-2-yl) isoquinolin-3- amine194

572 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.18 (s, 1H), 9.13 (s, 1H), 8.77(s, 1H), 8.05 (d, 1H, J = 5.7 Hz), 7.73 (s, 1H), 6.47 (d, 1H, J = 5.7Hz), 4.89 (s, 1H), 4.74 (t, 1H, J = 7.6 Hz), 4.51-4.11 (m, 4H),3.83-3.57 (m, 3H), 3.57- 3.40 (m, 3H), 3.10 (q, 2H, J = 7.4 Hz), 2.92(q, 1H, J = 7.3 Hz), 1.75-1.69 (m, 1H), 1.64-1.54 (m, 1H), 1.49 (d, 3H,J = 6.0 Hz), 1.36-1.18 (m, 12H) OO; Peak 1 (3S,4R)-1-[4- ({8-[(2R,3S)-3-[(ethanesulfonyl) methyl]-2- methylazetidin- 1-yl]-5-(propan-2-yl)-2,6-naph- thyridin-3- yl}amino) pyrimidin-2-yl]- 3-fluoro-4-methyl- piperidin-4-ol 195

572 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.19 (s, 1H), 9.14 (s, 1H), 8.77(s, 1H), 8.05 (d, 1H, J = 5.6 Hz), 7.73 (s, 1H), 6.47 (d, 1H, J = 5.6Hz), 4.88 (s, 1H), 4.74 (t, 1H, J = 7.6 Hz), 4.51-4.38 (m, 1H),4.37-4.09 (m, 3H), 3.82- 3.43 (m, 6H), 3.10 (q, 2H, J = 7.4 Hz), 2.92(q, 1H, J = 7.3 Hz), 1.75-1.69 (m, 1H), 1.64-1.55 (m, 1H), 1.49 (d, 3H,J = 6.0 Hz), 1.35-1.26 (m, 6H), 1.30- 1.18 (m, 6H) OO; Peak 2(3R,4S)-1-[4- ({8-[(2R,3S)-3- [(ethanesulfonyl) methyl]-2-methylazetidin-1- yl]-5-(propan-2- yl)-2,6-naph- thyridin-3- yl}amino)pyrimidin-2-yl]- 3-fluoro-4- methyl- piperidin-4-ol 196

573 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.85 (s, 1H), 9.04 (s, 1H), 8.60(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.39 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.44 (d, 1H, J = 5.7 Hz), 5.00 (d, 1H, J = 6.5 Hz),4.86-4.51 (m, 4H), 4.19 (t, 1H, J = 6.3 Hz), 3.75-3.37 (m, 7H),3.20-3.01 (m, 6H), 2.89 (q, 1H, J = 7.3 Hz), 1.84-1.63 (m, 2H),1.49-1.20 (m, 9H) B; Peak 2 (3S,4R)-3- fluoro-1-[4- ({5-[(2S)-1-hydroxypropan- 2-yl]-8- [(2S,3R)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methyl-piperidin-4-ol or (3S,4R)-3- fluoro-1-[4-({5- [(2R)-1-

hydroxypropan- 2-yl]-8- [(2S,3R)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methyl-piperidin-4-ol 197

573 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.05 (s, 1H), 8.63(s, 1H), 8.01 (d, 1H, J = 5.7 Hz), 7.40 (d, 1H, J = 7.9 Hz), 6.57 (d,1H, J = 8.0 Hz), 6.47 (d, 1H, J = 5.7 Hz), 4.84 (s, 1H), 4.73-4.59 (m,2H), 4.46-4.06 (m, 4H), 3.59 (s, 8H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.1Hz), 1.77-1.71 (m, 1H), 1.64- 1.55 (m, 1H), 1.43 (d, 3H, J = 6.0 Hz),1.31-1.21 (m, 6H) B; Peak 2 (3R,4S)-3- fluoro-1-[4- ({5-[(2S)-1-hydroxypropan- 2-yl]-8- [(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methyl-piperidin-4-ol or (3R,4S)-3- fluoro-1-[4- ({5-[(2R)-1-

hydroxypropan- 2-yl]-8- [(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methyl-piperidin-4-ol 198

573 1H NMR (400 MHz, MeOD-d4) δ 9.10 (s, 1H), 8.62 (s, 1H), 7.97 (d, J =5.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.41(d, J = 5.6 Hz, 1H), 4.74-4.55 (m, 4H), 4.45- 4.40 (m, 1H), 4.32-4.25(m, 1H), 3.89-3.85 (m, 1H), 3.80-3.70 (m, 1H), 3.66- 3.47 (m, 8H),3.39-3.33 (m, 1H), 3.01 (s, 3H), 1.49 (d, J = 6.0 Hz, 3H), 1.35 (d, J =6.8 Hz, 6H) (3R,4R,5S)-5- fluoro-1-(4-((5- isopropyl-8- ((2R,3S)-2-methyl-3- ((methylsulfonyl) methyl)azetidin- 1-yl)isoquinolin-3-yl)amino) pyrimidin-2-yl)- 4-methoxy- piperidin-3-ol and (3S,4S,5R)-5-fluoro-1-(4- ((5-isopropyl-8- ((2R,3S)-2- methyl-3-

((methylsulfonyl) methyl)azetidin- 1-yl)isoquinolin- 3-yl)amino)pyrimidin-2-yl)- 4-methoxy- piperidin-3-ol 199

573 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.02 (s, 1H), 8.61(s, 1H), 7.98 (d, 1H, J = 5.7 Hz), 7.38 (d, 1H, J = 8.0 Hz), 6.54 (d,1H, J = 8.0 Hz), 6.45 (d, 1H, J = 5.6 Hz), 4.81 (s, 1H), 4.67-4.59 (m,2H), 4.49-3.98 (m, 4H), 3.76-3.39 (m, 8H), 2.98 (s, 3H), 2.87 (q, 1H, J= 7.6 Hz), 1.74-1.68 (m, 1H), 1.55-1.49 (m, 1H), 1.40 (d, 3H, J = 6.0Hz), 1.28-1.19 (m, 6H) B; Peak 2 (3S,4R)-3-fluoro- 1-[4-({5-[(2S)-1-hydroxypropan- 2-yl]-8- [(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methyl-piperidin-4-ol or (3S,4R)-3- fluoro-1-[4-({5- [(2R)-1- hydroxypropan-

2-yl]-8- [(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methyl- piperidin-4-ol200

573 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.62 (s, 1H), 7.98 (d, J =5.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.42(d, J = 5.6 Hz, 1H), 4.65-4.60 (m, 2H), 4.54-4.21 (m, 4H), 3.72-3.65 (m,1H), 3.64-3.61 (m, 2H), 3.56- 3.44 (m, 5H), 3.43 (s, 3H), 3.01 (s, 3H),1.49 (d, J = 6.0 Hz, 3H), 1.36 (d, J = 6.7 Hz, 6H) (3R,4S,5S)-3-fluoro-1-(4-((5- isopropyl-8- ((2R,3S)-2- methyl-3- ((methylsulfonyl)methyl)azetidin- 1-yl)isoquinolin- 3-yl)amino) pyrimidin-2-yl)-5-methoxy- piperidin-4-ol and (3S,4R,5R)- 3-fluoro-1-(4-((5-isopropyl-8- ((2R,3S)-2- methyl-3-

((methylsulfonyl) methyl)azetidin- 1-yl)isoquinolin- 3-yl)amino)pyrimidin-2-yl)- 5-methoxy- piperidin-4-ol 201

573 1H NMR (400 MHz, MeOD-d4) δ 9.12 (s, 1H), 8.61 (s, 1H), 8.00 (d, J =5.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 6.55 (d, J = 7.6 Hz, 1H), 6.44(d, J = 5.6 Hz, 1H), 4.46- 4.34 (m, 4H), 4.10-4.01 (m, 3H), 3.75-3.70(m, 1H), 3.63-3.60 (m, 6H), 3.56-3.49 (m, 2H), 3.45 (s, 3H), 3.44-3.40(m, 2H), 3.08-3.06 (m, 1H), 3.04 (s, 3H), 1.37 (dd, J = 2.8, 6.8 Hz, 6H)(3R,4S,5S)-3- fluoro-1-(4-((5- isopropyl-8- ((2R,3S)-2- methyl-3-((methylsulfonyl) methyl)azetidin- 1-yl)isoquinolin- 3-yl)amino)pyrimidin-2-yl)- 5-methoxy piperidin-4-ol and (3S,4R,5R)- 3-fluoro-1-(4-((5-isopropyl-8- ((2R,3S)-2- methyl-3- ((methylsulfonyl)

methyl)azetidin- 1-yl)isoquinolin- 3-yl)amino) pyrimidin-2-yl)-5-methoxy piperidin-4-ol 202

573 1H NMR (400 MHz, MeOD-d4) δ 9.10 (s, 1H), 8.61 (s, 1H), 7.97 (d, J =5.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.40(d, J = 5.6 Hz, 1H), 4.74-4.55 (m, 4H), 4.45- 4.40 (m, 1H), 4.32-4.25(m, 1H), 3.89-3.85 (m, 1H), 3.80-3.70 (m, 1H), 3.66-3.47 (m, 8H), 3.39-3.33 (m, 1H), 3.01 (s, 3H), 1.49 (d, J = 6.0 Hz, 3H), 1.35 (d, J = 6.8Hz, 6H) P; Peak 2 (3S,4S,5R)-5- fluoro-1-[4-({8- [(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-olor (3R,4R,5S)-5- fluoro-1-[4-({8- [(2R,3S)-3- (methanesulfonyl-methyl)-2-

methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol 203

573 1H NMR (400 MHz, MeOD-d4) δ 9.10 (s, 1H), 8.62 (s, 1H), 7.97 (d, J =5.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.41(d, J = 5.6 Hz, 1H), 4.74-4.55 (m, 4H), 4.45-4.40 (m, 1H), 4.32-4.25 (m,1H), 3.89- 3.85 (m, 1H), 3.80-3.70 (m, 1H), 3.66-3.47 (m, 8H), 3.39-3.33(m, 1H), 3.01 (s, 3H), 1.49 (d, J = 6.0 Hz, 3H), 1.35 (d, J = 6.8 Hz,6H) P; Peak 1 (3R,4R,5S)-5- fluoro-1-[4-({8- [(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-olor (3S,4S,5R)-5- fluoro-1-[4-({8- [(2R,3S)-3- (methanesulfonyl-methyl)-2-

methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol 204

573 1H NMR (400 MHz, MeOD-d4) δ 9.01 (s, 1H), 8.52 (s, 1H), 7.88 (d, J =5.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.32(d, J = 5.6 Hz, 1H), 4.59-4.48 (m, 4H), 4.43-4.26 (m, 2H), 4.20-4.05 (m,1H), 3.61-3.56 (m, 1H), 3.56- 3.45 (m, 3H), 3.45-3.32 (m, 6H), 3.30-3.24(m, 1H), 2.91 (s, 3H), 1.39 (d, J = 6.0 Hz, 3H), 1.26 (dd, J = 3.2, 6.8Hz, 6H) Q; Peak 1 (3S,4R,5R)-3- fluoro-1-[4-({8- [(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 5-methoxy- piperidin-4-olor (3R,4S,5S)-3- fluoro-1-[4-({8- [(2R,3S)-3- (methanesulfonyl-methyl)-2-

methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 5-methoxy- piperidin-4-ol 205

573 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.91 (s, 1H), 9.05 (s, 1H), 8.63(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.1 Hz), 6.48 (d,1H, J = 5.6 Hz), 6.42 (d, 1H, J = 8.1 Hz), 5.08-4.72 (m, 2H), 4.66 (t,1H, J = 5.2 Hz), 4.52 (s, 1H), 4.39 (t, 2H, J = 7.7 Hz), 3.97 (t, 2H, J= 6.8 Hz), 3.82-3.65 (m, 1H), 3.64-3.43 (m, 7H), 3.29- 3.23 (m, 3H),3.02 (s, 3H), 1.85-1.79 (m, 2H), 1.31 (dd, 6H, J = 6.8, 3.2 Hz)2-{[(3S,4R)-3- fluoro-1-[4- ({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5- (propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]piperidin-4-yl] oxy}ethan-1-ol 206

573 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.45 (s, 1H), 9.10 (s, 1H), 8.62(s, 1H), 8.09 (d, 1H, J = 5.6 Hz), 6.52 (d, 1H, J = 5.6 Hz), 5.11-4.81(m, 2H), 4.75-4.61 (m, 2H), 4.46 (d, 1H, J = 13.3 Hz), 4.06 (t, 1H, J =7.3 Hz), 3.72-3.41 (m, 5H), 3.37 (s, 3H), 3.09 (q, 2H, J = 7.5 Hz), 2.95(p, 1H, J = 7.1 Hz), 1.89-1.69 (m, 2H), 1.54 (d, 3H, J = 6.2 Hz), 1.36(dd, 6H, J = 11.0, 6.7 Hz), 1.23 (t, 3H, J = 7.4 Hz) N-{4- [(2R,3S)-3-[(ethanesulfonyl) methyl]-2- methylazetidin- 1-yl]-1-(propan-2-yl)pyrido[3,4- d]pyridazin-7- yl}-2-[(3S,4R)- 3-fluoro-4- methoxy-piperidin-1-yl] pyrimidin-4- amine 207

573 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.44 (s, 1H), 9.10 (s, 1H), 8.61(s, 1H), 8.09 (d, 1H, J = 5.6 Hz), 6.52 (d, 1H, J = 5.6 Hz), 5.13-4.82(m, 2H), 4.67 (td, 3H, J = 12.6, 11.9, 5.9 Hz), 4.47 (d, 1H, J = 13.6Hz), 4.06 (t, 1H, J = 7.3 Hz), 3.69-3.48 (m, 7H), 3.40-3.34 (m, 2H),3.09 (q, 2H, J = 7.4 Hz), 2.94 (q, 1H, J = 7.2 Hz), 1.85-1.65 (m, 2H),1.54 (d, 3H, J = 6.1 Hz), 1.36 (dd, 6H, J = 6.8, 2.9 Hz), 1.23 (t, 3H, J= 7.4 Hz) N-{4- [(2R,3S)-3- [(ethanesulfonyl) methyl]-2- methylazetidin-1-yl]-1-(propan- 2-yl)pyrido[3,4- d]pyridazin-7- yl}-2-[(3R,4S)-3-fluoro-4- methoxy- piperidin-1-yl] pyrimidin-4- amine 208

574 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.12 (s, 1H), 9.04 (s, 1H), 8.54(s, 1H), 8.05 (d, 1H, J = 5.6 Hz), 7.97 (s, 1H), 6.59-6.46 (m, 1H), 4.99(d, 1H, J = 53.8 Hz), 4.87-4.65 (m, 3H), 4.60-4.46 (m, 2H), 3.99 (t, 1H,J = 7.3 Hz), 3.74-3.42 (m, 6H), 3.36 (s, 3H), 3.30-3.24 (m, 1H), 2.99(s, 3H), 2.89 (q, 1H, J = 7.2 Hz), 1.89-1.64 (m, 2H), 1.50 (d, 3H, J =6.1 Hz), 1.29 (d, 3H, J = 6.8 Hz) F; Peak 1 (2R)-2-[6-({2- [(3R,4S)-3-fluoro-4- methoxy- piperidin-1-yl] pyrimidin-4- yl}amino)-1- [(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-2,7-naph-thyridin-4-yl] propan-1-ol or (2S)-2-[6-({2- [(3R,4S)-3- fluoro-4-

methoxy- piperidin-1-yl] pyrimidin-4- yl}amino)-1- [(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-2,7-naph-thyridin-4-yl] propan-1-ol 209

575 1H NMR (400 MHz, 6d- DMSO) δ ppm 10.46 (s, 1H), 9.05 (s, 1H), 8.48(s, 1H), 8.09 (d, 1H, J = 5.6 Hz), 6.59 (d, 1H, J = 5.7 Hz), 4.62 (t,2H, J = 8.4 Hz), 4.49 (t, 2H, J = 7.7 Hz), 4.41-4.21 (m, 3H), 4.11-3.84(m, 2H), 3.77- 3.48 (m, 4H), 3.01 (s, 3H), 2.77 (dt, 1H, J = 11.5, 7.5Hz), 2.53 (t, 1H, J = 5.9 Hz), 2.06 (m, 2H), 1.41- 1.28 (m, 6H) MM, Peak2 (S)-N-(2-(5,5- difluoro-1-oxa- 7-azaspiro[3.5] nonan-7-yl)pyrimidin-4-yl)- 1-isopropyl-4- (3-((methyl- sulfonyl)methyl)azetidin-1- yl)pyrido[3,4- d]pyridazin-7- amine or (R)-N-(2-(5,5-difluoro- 1-oxa-7- azaspiro[3.5] nonan-7-yl)

pyrimidin-4-yl)- 1-isopropyl-4- (3-((methyl- sulfonyl)methyl)azetidin-1- yl)pyrido[3,4- d]pyridazin-7- amine 210

575 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.95 (s, 1H), 9.04 (s, 1H), 8.59(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.55 (d,1H, J = 8.1 Hz), 6.49 (d, 1H, J = 5.6 Hz), 5.53 (s, 1H), 4.73 (d, 1H, J= 10.4 Hz), 4.64 (t, 1H, J = 7.6 Hz), 4.46 (d, 1H, J = 12.3 Hz), 4.18(t, 1H, J = 6.2 Hz), 3.76-3.36 (m, 5H), 2.98 (s, 3H), 2.87 (q, 1H, J =7.1 Hz), 1.75-1.69 (m, 2H), 1.41 (d, 3H, J = 6.0 Hz), 1.32-1.19 (m, 9H)ppm E; Peak 1 (4S)-3,3- difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 4-methyl- piperidin-4-ol or (4R)-3,3-difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-

methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 4-methyl- piperidin-4-ol 211

575 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.96 (s, 1H), 9.04 (s, 1H), 8.59(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.55 (d,1H, J = 8.1 Hz), 6.49 (d, 1H, J = 5.7 Hz), 5.52 (s, 1H), 4.73 (s, 1H),4.64 (t, 1H, J = 7.5 Hz), 4.46 (d, 1H, J = 13.2 Hz), 4.18 (t, 1H, J =6.3 Hz), 3.76-3.53 (m, 2H), 3.57-3.31 (m, 3H), 2.98 (s, 3H), 2.87 (q,1H, J = 7.1 Hz), 1.74-1.68 (m, 2H), 1.41 (d, 3H, J = 6.0 Hz), 1.32-1.22(m, 9H) E; Peak 2 (4R)-3,3- difluoro-1-[4- ({8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methyl- piperidin-4-ol or(4S)-3,3- difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-

methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 4-methyl- piperidin-4-ol 212

575 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.97 (s, 1H), 9.07 (s, 1H), 8.58(s, 1H), 8.02 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.62- 6.50(m, 2H), 5.87 (d, 1H, J = 5.2 Hz), 4.93-4.56 (m, 2H), 4.35-3.78 (m, 6H),3.71-3.46 (m, 4H), 3.00 (s, 3H), 2.96-2.85 (m, 1H), 1.43 (d, 4H, J = 5.2Hz), 1.38- 1.25 (m, 8H) I; Peak 2 (3R,4R,5R)-3,5- difluoro-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 3-methyl-piperidin-4-ol or (3S,4S,5S)- 3,5-difluoro-1- [4-({8- [(2R,3S)-3-(methanesulfonyl-

methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 3-methyl- piperidin-4-ol 213

575 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.13 (s, 1H), 9.08 (s, 1H), 8.50(s, 1H), 8.01 (d, 1H, J = 5.9 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.60 (s,1H), 6.44 (d, 1H, J = 8.1 Hz), 5.75 (s, 1H), 4.70 (q, 1H, J = 11.5 Hz),4.39 (t, 2H, J = 7.6 Hz), 4.17 (d, 1H, J = 13.3 Hz), 3.97 (t, 2H, J =6.9 Hz), 3.87-3.67 (m, 1H), 3.68-3.45 (m, 4H), 3.32-3.22 (m, 2H), 3.01(s, 3H), 1.29 (dd, 6H, J = 6.7, 3.3 Hz), 1.00 (s, 3H), 0.89 (s, 3H) L;Peak 1 (4S)-3,3- difluoro-1- [4-({8-[3- (methanesulfonyl-methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino)pyrimidin-2-yl]- 5,5-dimethyl- piperidin-4-ol or (4R)-3,3-difluoro-1-[4- ({8-[3- (methane- sulfonylmethyl) azetidin-1-yl]-

5-(propan-2- yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]- 5,5-dimethyl-piperidin-4-ol 214

576 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.23 (s, 1H), 9.14 (s, 1H), 8.73(s, 1H), 8.06 (d, 1H, J = 5.7 Hz), 7.74 (s, 1H), 6.51 (d, 1H, J = 5.7Hz), 5.58 (s, 1H), 4.74 (t, 2H, J = 7.6 Hz), 4.54-4.44 (m, 1H), 4.27(dt, 1H, J = 27.4, 6.4 Hz), 3.83-3.38 (m, 6H), 3.01 (s, 3H), 2.93 (q,1H, J = 7.4 Hz), 1.77-1.71 (m, 2H), 1.49 (d, 3H, J = 6.1 Hz), 1.35-1.25(m, 9H) FF, Peak 2 (4R)-3,3- difluoro-1-[4- ({8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)-2,6-naph- thyridin-3- yl}amino) pyrimidin-2-yl]- 4-methyl-piperidin-4-ol or (4S)-3,3- difluoro-1-[4- ({8-[(2R,3S)-3-

(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)-2,6-naph- thyridin-3- yl}amino) pyrimidin-2-yl]- 4-methyl-piperidin-4-ol 215

576 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.17 (s, 1H), 9.04 (s, 1H), 8.49(s, 1H), 8.06 (d, 1H, J = 5.6 Hz), 8.00 (s, 1H), 6.55 (d, 1H, J = 5.6Hz), 5.56 (s, 1H), 4.86 (t, 1H, J = 8.0 Hz), 4.75-4.69 (m, 1H),4.60-4.40 (m, 2H), 3.98 (t, 1H, J = 7.3 Hz), 3.67 (dd, 1H, J = 30.1,13.3 Hz), 3.57-3.48 (m, 2H), 3.38 (dd, 2H, J = 13.4, 6.7 Hz), 2.98 (s,3H), 2.89 (q, 1H, J = 7.2 Hz), 1.75-1.69 (m, 2H), 1.49 (d, 3H, J = 6.1DD, Peak 2 (4R)-3,3- difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-yl}amino) pyrimidin-2-yl]- 4-methyl- piperidin-4-ol or (4S)-3,3-difluoro-1-[4- ({8-[(2R,3S)-3-

Hz), 1.35-1.23 (m, 9H) (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)-2,7-naph- thyridin-3- yl}amino) pyrimidin-2-yl]-4-methyl- piperidin-4-ol 216

577 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.13 (s, 1H), 9.10 (s, 1H), 8.67(s, 1H), 8.03 (d, 1H, J = 5.7 Hz), 7.34 (t, 1H, J = 9.3 Hz), 6.45 (d,2H, J = 6.7 Hz), 4.91 (d, 1H, J = 50.0 Hz), 4.73-4.67 (m, 2H), 4.47 (d,1H, J = 13.5 Hz), 4.21 (s, 1H), 3.81-3.39 (m, 10H), 3.27 (s, 3H), 3.01(s, 3H), 2.93-2.87 (m, 1H), 1.83-1.77 (m, 2H), 1.42 (d, 3H, J = 5.9 Hz)M; Peak 1 5-fluoro-N- {2-[(3R,4S)- 3-fluoro-4-(2- methoxyethoxy)piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]isoquinolin-3- amine 217

577 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.13 (s, 1H), 9.10 (s, 1H), 8.67(s, 1H), 8.03 (d, 1H, J = 5.6 Hz), 7.40-7.28 (m, 1H), 6.46 (t, 2H, J =5.4 Hz), 4.91 (d, 1H, J = 49.0 Hz), 4.75-4.64 (m, 2H), 4.46 (d, 1H, J =13.1 Hz), 4.21 (t, 1H, J = 6.0 Hz), 3.77-3.72 (m, 2H), 3.67 (q, 3H, J =4.8, 3.9 Hz), 3.61- 3.43 (m, 5H), 3.28 (s, 3H), 3.01 (s, 3H), 2.89 (d,1H, J = 7.3 Hz), 1.83-1.77 (m, 2H), 1.42 (d, 3H, J = 6.0 Hz) M; Peak 25-fluoro-N-{2- [(3S,4R)-3- fluoro-4-(2- methoxyethoxy) piperidin-1-yl]pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin- 1-yl]isoquinolin- 3-amine 218

576.2 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.48 (s, 1H), 8.08 (d, J =5.6 Hz, 1H), 7.46-7.37 (m, 2H), 6.43 (d, J = 7.6 Hz, 1H), 6.28 (d, J =5.5 Hz, 1H), 4.96-4.83 (m, 1H), 4.71 (dd, J = 13.2, 4.4 Hz, 1H), 4.46(t, J = 7.2 Hz, 2H), 4.07-3.94 (m, 3H), 3.70 (s, 3H), 3.69-3.55 (m, 3H),3.50-3.38 (m, 3H), 3.28- 3.18 (m, 1H), 2.99 (s, 3H), 2.45 (d, J = 10.2Hz, 1H), 1.37 (t, J = 6.8 Hz, 6H) BB Peak 2 (3R,4R)-5,5- difluoro-1-[4-({8-[3- (methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan-2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-olor (3S,4S)-5,5- difluoro-1-[4- ({8-[3-(methane- sulfonylmethyl)azetidin-1-yl]- 5-(propan-2-yl) isoquinolin-3-

yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol 219

579 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.86 (s, 1H), 9.05 (s, 1H), 8.61(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 7.9 Hz), 7.17 (t,1H, J = 51.8 Hz), 6.51-6.38 (m, 2H), 5.04 (d, 1H, J = 6.3 Hz), 4.82-4.64(m, 2H), 4.39 (t, 2H, J = 7.4 Hz), 4.05-3.90 (m, 4H), 3.66-3.45 (m, 2H),3.23-3.02 (m, 3H), 1.77-1.70 (m, 2H), 1.49-1.25 (m, 9H) NN; Peak 1(3S,4R)-1-[4- ({8-[3-(difluoro- methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]-3-fluoro-3- methyl- piperidin-4-ol 220

580 1H NMR (300 MHz, 6d- DMSO) δ ppm 10.06 (s, 1H), 9.00 (s, 1H), 8.47(s, 1H), 8.01 (d, 1H, J = 5.7 Hz), 7.98 (s, 1H), 7.14 (t, 1H, J = 51.9Hz), 6.49 (d, 1H, J = 5.7 Hz), 5.02 (d, 1H, J = 6.4 Hz), 4.83-4.45 (m,3H), 4.23 (t, 2H, J = 7.5 Hz), 3.92 (d, 2H, J = 7.4 Hz), 3.66-3.46 (m,1H), 3.45-3.02 (m, 4H), 1.71 (s, 2H), 1.46-1.18 (m, 9H) NN; Peak 1(3S,4R)-1-[4- ({8-[3-(difluoro- methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)-2,7-naph- thyridin-3- yl}amino) pyrimidin-2-yl]-3-fluoro-3- methyl- piperidin-4-ol 221

582 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.04 (s, 1H), 8.68 (s, 1H), 8.40(s, 2H), 8.00 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.42 (d, 1H, J = 5.7 Hz), 4.65 (t, 1H, J = 7.5 Hz),4.36 (d, 2H, J = 12.8 Hz), 4.24-4.14 (m, 1H), 3.69-3.59 (m, 3H), 3.27(t, 2H, J = 11.9 Hz), 3.18 (s, 3H), 2.99 (s, 3H), 2.90-2.77 (m, 3H),1.84-1.74 (m, 4H), 1.53-1.47 (m, 2H), 1.42 (d, 3H, J = 6.0 Hz), 1.29 (d,6H, J = 6.6 Hz) N-{2-[4-(2- aminoethyl)-4- methoxy- piperidin-1-yl]pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine 222

583 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.01 (s, 1H), 9.12 (s, 1H), 8.54(s, 1H), 8.01 (d, 1H, J = 5.6 Hz), 7.84 (d, 1H, J = 8.5 Hz), 6.53-6.43(m, 3H), 4.97 (d, 1H, J = 6.4 Hz), 4.88 (t, 1H, J = 8.2 Hz), 4.73 (dd,2H, J = 23.9, 15.2 Hz), 4.40 (t, 1H, J = 6.1 Hz), 3.97 (t, 1H, J = 7.2Hz), 3.65-3.45 (m, 3H), 3.09-2.98 (m, 5H), 2.93 (d, 1H, J = 7.5 Hz),1.73-1.68 (m, 2H), 1.49 (d, 3H, J = 6.1 Hz), 1.35 (d, 3H, J = 21.2 Hz)NN; Peak 1 (3S,4R)-3- fluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5- (trifluoromethyl) isoquinolin-3-yl}amino) pyrimidin-2-yl]- 3-methyl- piperidin-4-ol 223

584 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.85 (s, 1H), 9.05 (s, 1H), 8.60(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.47 (d,1H, J = 5.7 Hz), 6.41 (d, 1H, J = 8.0 Hz), 5.02 (d, 1H, J = 6.4 Hz),4.82-4.64 (m, 2H), 4.38 (dd, 3H, J = 8.9, 6.1 Hz), 3.95 (t, 2H, J = 6.9Hz), 3.79 (dd, 2H, J = 8.7, 6.7 Hz), 3.64 (t, 2H, J = 8.6 Hz), 3.62-3.45(m, 4H), 3.29-3.04 (m, 4H), 1.78-1.70 (m, 2H), 1.46-1.24 (m, 9H) NN;Peak 1 (3S,4R)-1-{4- [(8-{3- [(azetidine-3- sulfonyl)methyl]azetidin-1-yl}- 5-(propan-2- yl)isoquinolin- 3-yl)amino]pyrimidin-2-yl}- 3-fluoro-3- methyl- piperidin-4-ol 224

584 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.17 (s, 1H), 9.14 (s, 1H), 8.75(s, 1H), 8.04 (d, 1H, J = 5.6 Hz), 7.73 (s, 1H), 6.47 (d, 1H, J = 5.7Hz), 5.00 (d, 1H, J = 49.9 Hz), 4.88-4.69 (m, 2H), 4.56 (d, 1H, J = 13.7Hz), 4.32 (t, 1H, J = 6.2 Hz), 3.93-3.65 (m, 3H), 3.66-3.40 (m, 4H),3.01 (s, 3H), 2.93 (q, 1H, J = 7.3 Hz), 1.87-1.76 (m, 2H), 1.48 (d, 3H,J = 6.0 Hz), 1.32 (d, 6H, J = 6.6 Hz), 0.58-0.44 (m, 4H) N-{2-[(3R,4S)-4-cyclopropoxy- 3-fluoro- piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)-2,6-naph- thyridin-3-amine 225

584 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.15 (s, 1H), 9.11 (s, 1H), 8.73(s, 1H), 8.02 (d, 1H, J = 5.7 Hz), 7.71 (s, 1H), 6.44 (d, 1H, J = 5.7Hz), 4.97 (d, 1H, J = 49.4 Hz), 4.81-4.66 (m, 2H), 4.54 (d, 1H, J = 14.2Hz), 4.34-4.24 (m, 1H), 3.92-3.63 (m, 3H), 3.59-3.36 (m, 4H), 2.98 (s,3H), 2.90 (q, 1H, J = 7.4 Hz), 1.84-1.78 (m, 2H), 1.46 (d, 3H, J = 6.0Hz), 1.35-1.18 (m, 6H), 0.56- 0.44 (m, 4H) N-{2-[(3S,4R)-4-cyclopropoxy- 3-fluoro- piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl-2,6-naph- thyridin-3-amine 226

585 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.59 (s, 1H), 8.07 (d, J =5.6 F Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.30- 7.28 (m, 1H), 6.42 (d, J= 8.0 Hz, 1H), 6.16 (d, J = 5.6 Hz, 1H), 4.46 (t, J = 7.6 Hz, 2H), 4.20-4.06 (m, 2H), 4.04-3.99 (m, 2H), 3.98-3.91 (m, 2H), 3.90-3.81 (m, 2H),(3R,4S)-1-[4- ({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]-4-(2-methoxy- ethoxy) piperidin-3-ol and (3S,4R)-1-

3.78-3.69 (m, 3H), 3.64- 3.58 (m, 3H), 3.50-3.46 (m, 2H), 3.43 (s, 3H),3.10-3.04 (m, 1H), 2.99 (s, 3H), 2.09-2.01 (m, 1H), 1.83-1.74 (m, 1H),1.37 (dd, J = 6.8, 2.0 Hz, 6H) [4-({8-[3- (methanesulfonyl-methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino)pyrimidin-2-yl]- 4-(2-methoxy- ethoxy) piperidin-3-ol 227

585.3 1H NMR (400 MHz, CD3OD) δ = 9.11 (s, 1H), 8.67 (s, 1H), 7.98 (d, J= 6.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 6.38(d, J = 5.6 Hz, 1H), 4.66-4.63 (m, 1H), 4.57-4.54 (m, 1H), 4.43 (t, J =7.6 Hz, 2H), 4.03 (t, J = 6.8 Hz, 2H), 3.89-3.74 (m, 2H), 3.67-3.56 (m,(3S,4S)-1-[4- ({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]-4-(2-methoxy- ethoxy) piperidin-3-ol and (3R,4R)-1- [4-({8-[3-

6H), 3.51-3.44 (m, 1H), 3.42 (s, 3H), 3.39- 3.35 (m, 1H), 3.27-3.22 (m,1H), 3.16-3.11 (m, 1H), 3.04 (s, 3H), 2.21- 2.14 (m, 1H), 1.58-1.48 (m,1H), 1.38 (dd, J = 6.8, 5.2 Hz, 6H) (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]-4-(2-methoxy- ethoxy) piperidin-3-ol 228

587 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.05 (s, 1H), 8.64(s, 1H), 7.99 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.46 (d, 1H, J = 5.7 Hz), 4.93 (d, 1H, J = 50.4 Hz),4.82-4.72 (m, 1H), 4.70-4.61 (m, 2H), 4.53 (d, 1H, J = 13.0 Hz), 4.19(p, 1H, J = 6.2 Hz), 3.73 (dd, 1H, J = 26.1, 9.6 Hz), 3.67-3.35 (m, 9H),3.24 (d, 1H, J = 11.5 Hz), 2.99 (s, 3H), 2.89 (p, 1H, J = 7.4 Hz),1.89-1.69 (m, 2H), 1.42 (d, 2-{[(3R,4S)-3- fluoro-1-[4- ({8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl] piperidin-4-yl]oxy}ethan-1-ol 3H, J = 6.0 Hz), 1.31 (t, 6H, J = 6.5 Hz) 229

587 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.05 (s, 1H), 8.64(s, 1H), 7.99 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.46 (d, 1H, J = 5.7 Hz), 5.04-4.84 (m, 1H), 4.76 (t,1H, J = 7.9 Hz), 4.70-4.61 (m, 2H), 4.53 (d, 1H, J = 13.1 Hz), 4.19 (p,1H, J = 6.1 Hz), 3.81-3.67 (m, 1H), 3.67-3.57 (m, 1H), 3.61-3.38 (m,8H), 3.29- 3.17 (m, 1H), 2.99 (s, 3H), 2.88 (h, 1H, J = 7.3 Hz), 1.83(dd, 1H, J = 13.1, 4.4 Hz), 2-{[(3S,4R)-3- fluoro-1-[4- ({8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl] piperidin-4-yl]oxy}ethan-1-ol 1.76 (d, 1H, J = 10.9 Hz), 1.42 (d, 3H, J = 6.1 Hz), 1.31(dd, 6H, J = 6.8, 2.5 Hz) 230

590 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.20 (s, 1H), 9.05 (s, 1H), 8.50(s, 1H), 8.07 (d, 1H, J = 5.7 Hz), 8.02 (s, 1H), 6.55 (d, 1H, J = 5.7Hz), 5.58 (s, 1H), 4.86 (t, 1H, J = 8.0 Hz), 4.76-4.70 (m, 1H), 4.56 (t,1H, J = 6.3 Hz), 4.47 (d, 1H, J = 13.4 Hz), 3.98 (t, 1H, J = 7.3 Hz),3.68 (dd, 1H, J = 30.1, 13.3 Hz), 3.52 (d, 2H, J = 7.4 Hz), 3.45-3.39(m, 1H), 3.09 (q, 2H, J = 7.4 Hz), 2.89 (q, 1H, J = 7.3 Hz), 1.76-1.70(m, 2H), 1.50 (d, 3H, J = 6.1 Hz), 1.36-1.17 (m, 12H) GG, Peak 2(4R)-1-[4-({8- [(2R,3S)-3- [(ethanesulfonyl) methyl]-2- methylazetidin-1-yl]-5-(propan- 2-yl)-2,7-naph- thyridin-3- yl}amino) pyrimidin-2-yl]-3,3-difluoro-4- methyl- piperidin-4-ol or (4S)-1-[4- ({8-[(2R,3S)-3-[(ethanesulfonyl) methyl]-2-

methylazetidin- 1-yl]-5-(propan- 2-yl)-2,7-naph- thyridin-3- yl}amino)pyrimidin-2-yl]- 3,3-difluoro-4- methyl- piperidin-4-ol 231

590 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.23 (s, 1H), 9.14 (s, 1H), 8.73(s, 1H), 8.06 (d, 1H, J = 5.6 Hz), 7.74 (s, 1H), 6.51 (d, 1H, J = 5.7Hz), 5.59 (s, 1H), 4.74 (t, 2H, J = 7.5 Hz), 4.49 (d, 1H, J = 13.0 Hz),4.32 (t, 1H, J = 6.3 Hz), 3.83-3.58 (m, 3H), 3.61-3.45 (m, 2H),3.40-3.34 (m, 1H), 3.10 (q, 2H, J = 7.4 Hz), 2.92 (q, 1H, J = 7.3 Hz),1.78-1.72 (m, 2H), 1.49 (d, 3H, J = 6.0 Hz), 1.35-1.18 (m, 12H) O; Peak1 (in- ter- me- diate) (4R)-1-[4-({8- [(2R,3S)-3- [(ethanesulfonyl)methyl]-2- methylazetidin- 1-yl]-5-(propan- 2-yl)-2,6-naph- thyridin-3-yl}amino) pyrimidin-2-yl]- 3,3-difluoro-4- methyl- piperidin-4-ol or(4S)-1-[4- ({8-[(2R,3S)-3- [(ethanesulfonyl) methyl]-2-

methylazetidin- 1-yl]-5-(propan- 2-yl)-2,6-naph- thyridin-3- yl}amino)pyrimidin-2-yl]- 3,3-difluoro-4- methyl- piperidin-4-ol 232

591 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.00 (s, 1H), 9.06 (s, 1H), 8.53(s, 1H), 8.02 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.60-6.53(m, 2H), 5.31 (d, 1H, J = 5.8 Hz), 4.83-4.78 (m, 1H), 4.66 (t, 1H, J =7.5 Hz), 4.52 (dd, 1H, J = 12.5, 4.4 Hz), 4.19 (p, 1H, J = 6.1 Hz),3.79- 3.66 (m, 2H), 3.63 (t, 1H, J = 7.1 Hz), 3.57 (s, 3H), 3.55-3.44(m, 4H), 3.18 (t, 1H, J = 11.5 Hz), 2.99 (s, 3H), 2.88 (h, 1H, J = 7.3Hz), 1.42 (d, 3H, J = 6.0 Hz), 1.29 (dd, 6H, J = 14.0, F; Peak 1(3R,4R)-5,5- difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol or (3S,4S)-5,5-difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1-

6.7 Hz) yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]-4-methoxy- piperidin-3-ol 233

592 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.24 (s, 1H), 9.14 (s, 1H), 8.65(s, 1H), 8.07 (d, 1H, J = 5.6 Hz), 7.74 (s, 1H), 6.56 (d, 1H, J = 5.7Hz), 5.33 (d, 1H, J = 5.7 Hz), 4.74 (t, 2H, J = 7.6 Hz), 4.52 (d, 1H, J= 11.8 Hz), 4.32 (t, 1H, J = 6.3 Hz), 3.82-3.67 (m, 5H), 3.58 (s, 4H),3.52 (d, 1H, J = 13.9 Hz), 3.29-3.14 (m, 1H), 3.01 (s, 3H), 2.93 (q, 1H,J = 7.1 Hz), 1.48 (d, 3H, J = 6.0 Hz), 1.35-1.20 (m, 6H) K; Peak 1(3R,4R)-5,5- difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin- 1-yl]-5-(propan- 2-yl)-2,6-naph- thyridin-3- yl}amino)pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol or (3S,4S)-5,5-difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-

methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)-2,6-naph- thyridin-3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol 234

592 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.23 (s, 1H), 9.15 (s, 1H), 8.66(s, 1H), 8.07 (d, 1H, J = 5.6 Hz), 7.74 (s, 1H), 6.56 (d, 1H, J = 5.7Hz), 5.33 (d, 1H, J = 5.8 Hz), 4.74 (t, 2H, J = 7.6 Hz), 4.51 (d, 1H, J= 13.0 Hz), 4.32 (t, 1H, J = 6.2 Hz), 3.87-3.64 (m, 4H), 3.64-3.44 (m,6H), 3.29-3.14 (m, 1H), 3.01 (s, 3H), 2.93 (q, 1H, J = 7.2 Hz), 1.48 (d,3H, J = 6.0 Hz), 1.31 (dd, 6H, J = 11.0, 6.6 Hz) K; Peak 2 (3S,4S)-5,5-difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)-2,6-naph- thyridin-3- yl}amino)pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol or (3R,4R)-5,5-difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-

methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)-2,6-naph- thyridin-3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol 235

592 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.19 (s, 1H), 9.03 (s, 1H), 8.40(s, 1H), 8.05 (d, 1H, J = 5.6 Hz), 7.98 (s, 1H), 6.58 (d, 1H, J = 5.7Hz), 5.31 (d, 1H, J = 5.8 Hz), 4.84 (t, 1H, J = 7.9 Hz), 4.74 (s, 1H),4.58- 4.43 (m, 2H), 3.95 (t, 1H, J = 7.3 Hz), 3.73-3.63 (m, 3H),3.58-3.47 (m, 5H), 3.18 (t, 1H, J = 11.1 Hz), 2.97 (s, 3H), 2.87 (q, 1H,J = 7.5 Hz), 1.47 (d, 3H, J = 6.0 Hz), 1.29 (t, 6H, J = 6.3 Hz) K; Peak1 (3R,4R)-5,5- difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol or (3S,4S)-5,5-difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-

methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol 236

592 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.19 (s, 1H), 9.03 (s, 1H), 8.41(s, 1H), 8.06 (d, 1H, J = 5.6 Hz), 7.96 (s, 1H), 6.59 (d, 1H, J = 5.7Hz), 5.32 (d, 1H, J = 5.8 Hz), 4.88-4.82 (m, 1H), 4.76-4.70 (m, 1H),4.57-4.52 (m, 1H), 4.52-4.42 (m, 1H), 3.98 (s, 1H), 3.72- 3.66 (m, 3H),3.58-3.48 (m, 5H), 3.22-3.16 (m, 1H), 2.97 (s, 3H), 2.94-2.83 (m, 1H),1.48 (d, 3H, J = 6.1 Hz), 1.29 (dd, 6H, J = 8.7, 6.7 Hz) K; Peak 2(3S,4S)-5,5- difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph- thyridin-3- yl}amino)pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol or (3R,4R)-5,5-difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-

methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol 237

598 1H-NMR (400 MHz, 4d- CD3OD) δ ppm 9.21 (d, 1H, J = 0.7 Hz), 8.55 (s,1H), 8.01 (d, 1H, J = 5.8 Hz), 7.89 (s, 1H), 6.44 (d, 1H, J = 5.8 Hz),4.84-4.65 (m, 2H), 3.81 (dd, 1H, J = 14.4, 5.4 Hz), 3.70 (ddd, 1H, J =22.5, 10.0, 5.0 Hz), 3.58- 3.49 (m, 1H), 3.44 (p, 1H, J = 6.9 Hz),3.31-3.13 (m, 3H), 3.00 (dt, 1H, J = 8.6, 4.6 Hz), 2.30 (s, 1H), 1.90(t, 1H, J = 4.4 Hz), 1.64 (dt, 1H, J = 10.0, 5.2 Hz), 1.57-1.51 (m, 1H),1.48 (d, 3H, J = 21.1 Hz), 1.43-1.36 (m, 6H) NN; Peak 1 (3S,4R)-3-fluoro-3- methyl-1-(4- {[5-(propan-2- yl)-8-[3- (trifluoro-methanesulfonyl- methyl)azetidin- 1-yl]-2,7-naph- thyridin-3- yl]amino}pyrimidin-2-yl) piperidin-4-ol 238

598 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.85 (s, 1H), 9.05 (s, 1H), 8.60(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.47 (d,1H, J = 5.7 Hz), 6.41 (d, 1H, J = 8.0 Hz), 5.02 (d, 1H, J = 6.4 Hz),4.82-4.64 (m, 2H), 4.37 (t, 2H, J = 7.6 Hz), 4.18 (t, 1H, J = 7.1 Hz),3.95 (t, 2H, J = 6.7 Hz), 3.53 (d, 6H, J = 9.7 Hz), 3.25-3.14 (m, 2H),3.14-3.04 (m, 1H), 2.24 (s, 3H), 1.77-1.71 (m, 2H), 1.44-1.24 (m, 10H)NN; Peak 1 (3S,4R)-3- fluoro-3- methyl-1-(4- {[8-(3-{[(1-methylazetidin- 3-yl)sulfonyl] methyl}azetidin- 1-yl)-5-(propan- 2-yl)isoquinolin-3- yl]amino} pyrimidin-2-yl) piperidin-4-ol 239

600 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.83 (s, 1H), 9.03 (s, 1H), 8.58(s, 1H), 7.97 (d, 1H, J = 5.6 Hz), 7.40 (d, 1H, J = 8.0 Hz), 6.45 (d,1H, J = 5.7 Hz), 6.39 (d, 1H, J = 8.0 Hz), 5.00 (d, 1H, J = 6.4 Hz),4.80-4.61 (m, 2H), 4.37 (t, 2H, J = 7.4 Hz), 4.00-3.89 (m, 2H), 3.61 (d,NN; Peak 1 (3S,4R)-1-(4- {[8-(3-{[2- (dimethylamino) ethanesulfonyl]methyl}azetidin- 1-yl)-5-(propan- 2-yl)isoquinolin- 3-yl]amino}pyrimidin-2-yl)- 3-fluoro-3- 2H, J = 7.4 Hz), 3.58-3.41 methyl- (m, 2H),3.38-2.97 (m, 4H), piperidin-4-ol 2.65 (t, 2H, J = 6.9 Hz), 2.17 (s,6H), 1.75-1.68 (m, 2H), 1.42-1.21 (m, 9H) 240

600 1H-NMR (300 MHz, 4d- CD3OD) δ ppm 9.11 (s, 1H), 8.68 (s, 1H), 7.97(d, 1H, J = 5.8 Hz), 7.48 (d, 1H, J = 8.0 Hz), 6.66 (d, 1H, J = 8.0 Hz),6.38 (d, 1H, J = 5.8 Hz), 4.70-4.61 (m, 2H), 4.35 (s, 1H), 4.33-4.23 (m,1H), 3.89- 3.41 (m, 9H), 3.02 (s, 3H), 3.08-2.94 (m, 1H), 2.83 (t, 2H, J= 5.3 Hz), 2.46 (s, 3H), 2.01-1.82 (m, 2H), 1.50 (d, 3H, J = 6.1 Hz),1.37 (dd, 6H, J = 6.8, 4.4 N-{2-[(3S,4R)- 3-fluoro-4-[2- (methylamino)ethoxy] piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amineHz) 241

600 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.92 (s, 1H), 9.06 (s, 1H), 8.60(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.48 (d, 1H, J = 5.6 Hz), 4.80-4.60 (m, 3H), 4.20 (t,1H, J = 6.3 Hz), 3.69-3.46 (m, 6H), 3.44 (dd, 2H, J = 10.5, 4.7 Hz),3.24- 3.07 (m, 3H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.2 Hz), 2.71 (t, 2H,J = 5.8 Hz), 1.99-1.90 (m, 1H), 1.73-1.63 (m, 1H), 1.55-1.36 (m, 6H),1.31 (t, N-{2-[(3S,4R)- 4-(2- aminoethoxy)-3- fluoro-3- methylpiperidin-1-yl]pyrimidin- 4-yl}-8- [(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine 6H, J = 7.2Hz) 242

601 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.92 (s, 1H), 9.06 (s, 1H), 8.60(s, 1H), 7.99 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.47 (d, 1H, J = 5.7 Hz), 4.83-4.60 (m, 4H), 4.20 (t,1H, J = 6.3 Hz), 3.64 (dd, 2H, J = 9.9, 4.9 Hz), 3.59-3.37 (m, 7H),3.24-3.07 (m, 2H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.1 Hz), 2.01-1.91 (m,1H), 1.73-1.63 (m, 1H), 1.48-1.26 (m, 12H) NN; Peak 1 2-{[(3S,4R)-3-fluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino)pyrimidin-2-yl]- 3-methyl- piperidin-4-yl] oxy}ethan-1-ol 243

601 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.95 (s, 1H), 9.06 (s, 1H), 8.65(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.47 (d, 1H, J = 5.7 Hz), 4.94 (d, 1H, J = 50.4 Hz),4.78 (s, 1H), 4.67 (q, 2H, J = 5.7, 4.4 Hz), 4.55 (d, 1H, J = 13.3 Hz),4.20 (t, 1H, J = 6.3 Hz), 3.83-3.56 (m, 3H), 3.60-3.45 (m, 7H),3.35-3.19 (m, 1H), 3.10 (q, 2H, J = 7.4 Hz), 2.89 (q, 1H, J = 7.2 Hz),1.85-1.74 (m, 2H), 1.43 (d, 2-{[(3R,4S)-1- [4-({8- [(2R,3S)-3-[(ethanesulfonyl) methyl]-2- methylazetidin- 1-yl]-5-(propan-2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]- 3-fluoro- piperidin-4-yl]oxy}ethan-1-ol 3H, J = 6.0 Hz), 1.36-1.18 (m, 9H) 244

601 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.95 (s, 1H), 9.06 (s, 1H), 8.66(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.0 Hz), 6.47 (d, 1H, J = 5.7 Hz), 5.06-4.82 (m, 1H), 4.81-4.75(m, 1H), 4.66 (q, 2H, J = 4.7, 3.2 Hz), 4.55 (d, 1H, J = 13.2 Hz), 4.21(q, 1H, J = 6.5 Hz), 3.81-3.38 (m, 10H), 3.25 (t, 1H, J = 10.9 Hz), 3.10(q, 2H, J = 7.4 Hz), 2.90 (p, 1H, J = 7.1 Hz), 1.86-1.71 (m, 2H), 1.43(d, 3H, J = 6.0 Hz), 1.31 (dd, 6H, J = 6.8, 2-{[(3S,4R)-1-[4-({8-[(2R,3S)- 3-[(ethane- sulfonyl)methyl]- 2-methyl- azetidin-1-yl]-5-(propan-2- yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]- 3-fluoro-piperidin-4-yl] oxy}ethan-1-ol 2.4 Hz), 1.23 (t, 3H, J = 7.4 Hz) 245

601 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.06 (s, 1H), 8.65(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.47 (d, 1H, J = 5.7 Hz), 4.92 (d, 1H, J = 50.1 Hz),4.79-4.62 (m, 2H), 4.52 (d, 1H, J = 13.2 Hz), 4.25-4.15 (m, 1H),3.78-3.59 (m, 5H), 3.56-3.44 (m, 5H), 3.28 (s, 3H), 3.00 (s, 3H),2.93-2.85 (m, 1H), 1.83-1.77 (m, 2H), 1.43 (d, 3H, J = 6.0 Hz),1.36-1.26 K; Peak 1 N-{2-[(3S,4R)- 3-fluoro-4-(2- methoxyethoxy)piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine(m, 6H) 246

601 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.06 (s, 1H), 8.65(s, 1H), 8.00 (d, 1H, J = 5.5 Hz), 7.43 (d, 1H, J = 7.7 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.47 (d, 1H, J = 5.7 Hz), 4.92 (d, 1H, J = 50.6 Hz),4.80-4.60 (m, 2H), 4.52 (d, 1H, J = 12.6 Hz), 4.23-4.17 (m, 1H),3.71-3.65 (m, 4H), 3.70-3.61 (m, 1H), 3.57-3.44 (m, 5H), 3.28 (s, 3H),3.00 (s, 3H), 2.89 (d, 1H, J = 7.2 Hz), 1.84-1.78 (m, 2H), 1.43 (d, K;Peak 2 N-{2-[(3R,4S)- 3-fluoro-4-(2- methoxyethoxy) piperidin-1-yl]pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine 3H, J = 5.9Hz), 1.35-1.27 (m, 6H), 247

601 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.06 (s, 1H), 8.65(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.2 Hz), 6.47 (d, 1H, J = 5.7 Hz), 4.93 (d, 1H, J = 49.6 Hz),4.75-4.60 (m, 3H), 4.49-4.43 (m, 1H), 4.25-4.15 (m, 1H), 3.82- 3.40 (m,10H), 3.00 (s, 3H), 2.94-2.85 (m, 1H), 1.86- 1.72 (m, 2H), 1.43 (d, 3H,J = 6.0 Hz), 1.36-1.27 (m, 6H), 1.07 (d, 3H, J = 6.3 L; Peak 1(2S)-1-{[(3S,4R)- 3-fluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl] piperidin-4-yl] oxy}propan-2-ol or (2R)-1-{[(3S,4R)-3- fluoro-1-[4-({8-

Hz) [(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]piperidin-4-yl] oxy}propan-2-ol 248

601 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.2 (s, 1H), 9.07 (s, 1H), 8.65(s, 1H), 8.00 (d, 1H, J = 5.8 Hz), 7.44 (d, 1H, J = 8.0 Hz), 6.58 (d,1H, J = 8.0 Hz), 6.49 (s, 1H), 4.93 (d, 1H, J = 48.1 Hz), 4.73-4.61 (m,3H), 4.52-4.49 (m, 1H), 4.27-4.15 (m, 1H), 3.86-3.39 (m, 10H), 3.00 (s,3H), 2.91-2.89 (m, 1H), 1.85-1.79 (m, 2H), 1.43 (d, 3H, J = 6.0 Hz),1.31 (d, 6H, J = 6.6 Hz), 1.07 (d, 3H, J = 6.3 Hz) L; Peak 2(2R)-1-{[(3S,4R)- 3-fluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl] piperidin-4-yl] oxy}propan-2-ol or (2S)-1-{[(3S,4R)-3- fluoro-1-[4-

({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]piperidin-4-yl] oxy}propan-2-ol 249

602 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.12 (s, 1H), 9.03 (s, 1H), 8.52(s, 1H), 8.04 (d, 1H, J = 5.6 Hz), 8.00 (s, 1H), 6.50 (d, 1H, J = 5.6Hz), 5.05-4.80 (m, 2H), 4.78-4.63 (m, 2H), 4.60-4.46 (m, 2H), 3.97 (t,1H, J = 7.2 Hz), 3.80-3.63 (m, 1H), 3.62- 3.44 (m, 7H), 3.37-3.16 (m,2H), 3.08 (q, 2H, J = 7.4 Hz), 2.88 (d, 1H, J = 7.1 Hz), 1.85-1.79 (m,2H), 1.49 (d, 3H, J = 6.1 Hz), 1.32 (t, 6H, J = 6.9 Hz), 1.22 (t, 3H, J= 7.4 Hz) 2-{[(3S,4R)-1-[4- ({8-[(2R,3S)-3- [(ethanesulfonyl) methyl]-2-methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph- thyridin-3- yl}amino)pyrimidin-2-yl]- 3-fluoro- piperidin-4-yl] oxy}ethan-1-ol 250

602 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.13 (s, 1H), 9.03 (s, 1H), 8.52(s, 1H), 8.04 (d, 1H, J = 5.6 Hz), 8.00 (s, 1H), 6.50 (d, 1H, J = 5.7Hz), 4.93 (d, 1H, J = 48.7 Hz), 4.89-4.47 (m, 5H), 3.97 (t, 1H, J = 7.3Hz), 3.73 (dd, 1H, J = 25.2, 8.6 Hz), 3.52 (dd, 7H, J = 12.3, 7.1 Hz),3.35-3.18 (m, 2H), 3.08 (q, 2H, J = 7.4 Hz), 2.88 (q, 1H, J = 7.2 Hz),1.88-1.68 (m, 2H), 1.49 (d, 3H, J = 6.1 Hz), 1.32 (d, 6H, J = 6.7 Hz),1.22 (t, 3H, J = 7.4 Hz) 2-{[(3R,4S)-1- [4-({8- [(2R,3S)-3-[(ethanesulfonyl) methyl]-2- methylazetidin- 1-yl]-5-(propan- 2-yl)-2,7-naphthyridin-3- yl}amino) pyrimidin-2-yl]- 3-fluoro- piperidin-4-yl]oxy}ethan-1-ol 251

605 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.01 (s, 1H), 9.06 (s, 1H), 8.59(s, 1H), 8.02 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.55 (dd,2H, J = 10.9, 6.7 Hz), 4.69 (t, 2H, J = 7.0 Hz), 4.47-3.86 (m, 5H), 3.60(s, 9H), 2.99 (s, 3H), 2.93-2.87 (m, 1H), 2.00-1.94 (m, 1H), 1.81- 1.75(m, 1H), 1.42 (d, 3H, J = 6.0 Hz), 1.29 (dd, M; Peak 1 2-{[(4R)-3,3-difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl] piperidin-4-yl] oxy}ethan-1-ol or 2-{[(4S)-3,3-

6H, J = 7.2, 3.5 Hz) difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-yl}amino) pyrimidin-2-yl] piperidin-4-yl] oxy}ethan-1-ol 252

605 1H-NMR (300 MHz, 4d- CD3OD) δ ppm 9.14 (s, 1H), 8.62 (s, 1H), 7.99(d, 1H, J = 5.9 Hz), 7.49 (d, 1H, J = 8.0 Hz), 6.68 (d, 1H, J = 8.0 Hz),6.47 (d, 1H, J = 5.9 Hz), 4.68 (t, 1H, J = 7.5 Hz), 4.43 3.99 (m, 4H),3.87 (dd, 3H, J = 13.0, 6.8 Hz), 3.83-3.42 (m, 7H), 3.14-2.91 (m, 4H),2.05-2.02 (m, 2H), 1.51 (d, 3H, J = 6.1 Hz), M; Peak 2 2-{[(4S)-3,3-difluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl] piperidin-4-yl] oxy}ethan-1-ol or 2-{[(4R)-3,3-

1.37 (dd, 6H, J = 6.8, 1.3 Hz) difluoro-1-[4- ({8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl] piperidin-4-yl]oxy}ethan-1-ol 253

614 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.06 (s, 1H), 8.64(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.46 (d, 1H, J = 5.7 Hz), 4.92 (d, 1H, J = 49.8 Hz),4.76-4.61 (m, 2H), 4.49 (d, 1H, J = 13.3 Hz), 4.19 (t, 1H, J = 6.3 Hz),3.79-3.47 (m, 9H), 3.00 (s, 3H), 2.89 (d, 1H, J = 7.3 Hz), 2.46 (t, 2H,J = 6.0 Hz), 2.19 (s, 6H), 1.83-1.71 (m, 2H), 1.43 (d, 3H, J = 6.0 Hz),1.31 (dd, 6H, J = 6.7, N-{2-[(3R,4S)- 4-[2-(dimethyl- amino)ethoxy]-3-fluoro- piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- amine 5.0 Hz) 254

614 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.05 (s, 1H), 8.64(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.0 Hz), 6.46 (d, 1H, J = 5.7 Hz), 4.92 (d, 1H, J = 49.5 Hz),4.74-4.60 (m, 2H), 4.47 (d, 1H, J = 13.4 Hz), 4.19 (t, 1H, J = 6.3 Hz),3.80-3.43 (m, 9H), 2.99 (s, 3H), 2.88 (q, 1H, J = 7.2 Hz), 2.44 (t, 2H,J = 6.0 Hz), 2.17 (s, 6H), 1.82-1.76 (m, 2H), 1.42 (d, 3H, J = 6.0 Hz),1.30 (dd, 6H, J = 6.8, N-{2-[(3S,4R)- 4-[2-(dimethyl- amino)ethoxy]-3-fluoro- piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- amine 1.9 Hz) 255

615 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.05 (s, 1H), 8.65(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.46 (d, 1H, J = 5.7 Hz), 4.90 (d, 1H, J = 48.1 Hz),4.66 (s, 2H), 4.39 (d, 1H, J = 13.1 Hz), 4.35 (s, 1H), 4.23-4.15 (m,1H), 3.82-3.68 (m, 1H), 3.67- 3.37 (m, 7H), 2.99 (s, 3H), 2.88 (q, 1H, J= 7.3 Hz), 1.82-1.78 (m, 2H), 1.42 (d, 3H, J = 6.1 Hz), 1.30 (t, 6H, J =6.5 Hz), 1.11 (d, 6H, J = 1.1 Hz) 1-{[(3R,4S)-3- fluoro-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]piperidin-4-yl] oxy}-2-methyl- propan-2-ol 256

615 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.05 (s, 1H), 8.65(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.47 (d, 1H, J = 5.6 Hz), 4.90 (d, 1H, J = 50.5 Hz),4.66 (t, 1H, J = 7.5 Hz), 4.64-4.60 (m, 1H), 4.44-4.32 (m, 2H), 4.19 (t,1H, J = 6.3 Hz), 3.75 (d, 1H, J = 24.1 Hz), 3.68-3.35 (m, 7H), 2.99 (s,3H), 2.88 (q, 1H, J = 7.4 Hz), 1.83- 1.78 (m, 2H), 1.42 (d, 3H, J = 6.0Hz), 1.30 (dd, 6H, J = 6.8, 2.1 Hz), 1.11 (d, 6H, 1-{[(3S,4R)-3-fluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl] piperidin-4-yl] oxy}-2-methyl- propan-2-ol J = 1.6 Hz)257

616 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.16 (s, 1H), 9.13 (s, 1H), 8.76(s, 1H), 8.04 (d, 1H, J = 5.6 Hz), 7.73 (s, 1H), 6.46 (d, 1H, J = 5.8Hz), 4.92 (d, 1H, J = 50.7 Hz), 4.73 (t, 1H, J = 7.6 Hz), 4.65 (dd, 1H,J = 14.0, 7.5 Hz), 4.40 (d, 1H, J = 13.4 Hz), 4.35 (s, 1H), 4.30 (q, 1H,J = 6.3 Hz), 3.74 (dt, 3H, J = 18.9, 6.9 Hz), 3.57 (tq, 3H, J = 14.0,7.8, 6.8 Hz), 3.44- 3.32 (m, 2H), 3.00 (s, 3H), 2.93 (p, 1H, J = 7.4Hz), 1.81 (d, 2H, J = 4.7 1-{[(3R,4S)-3- fluoro-1-[4- ({8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)-2,6-naph- thyridin-3- yl}amino) pyrimidin-2-yl] piperidin-4-yl]oxy}-2- methyl- propan-2-ol Hz), 1.48 (d, 3H, J = 6.0 Hz), 1.31 (d,6H, J = 6.6 Hz), 1.11 (d, 6H, J = 1.1 Hz) 258

616 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.18 (s, 1H), 9.14 (s, 1H), 8.77(s, 1H), 8.04 (d, 1H, J = 5.6 Hz), 7.73 (s, 1H), 6.47 (d, 1H, J = 5.6Hz), 4.92 (d, 1H, J = 48.7 Hz), 4.73 (q, 1H, J = 6.6, 5.6 Hz), 4.68-4.60 (m, 1H), 4.46-4.27 (m, 3H), 3.83-3.50 (m, 6H), 3.45-3.36 (m, 2H),3.01 (s, 3H), 2.92 (p, 1H, J = 7.3 Hz), 1.85-1.79 (m, 2H), 1.48 (d, 3H,J = 6.0 Hz), 1.32 (t, 6H, J = 7.1 Hz), 1.12 (s, 6H) 1-{[(3S,4R)-3-fluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)-2,6-naph- thyridin-3- yl}amino)pyrimidin-2-yl] piperidin-4-yl] oxy}-2-methyl- propan-2-ol 259

616 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.13 (s, 1H), 9.04 (s, 1H), 8.52(s, 1H), 8.05 (d, 1H, J = 5.6 Hz), 8.01 (s, 1H), 6.51 (d, 1H, J = 5.6Hz), 5.01-4.79 (m, 2H), 4.66-4.49 (m, 2H), 4.38 (d, 1H, J = 13.2 Hz),4.34 (s, 1H), 3.98 (t, 1H, J = 7.3 Hz), 3.75 (d, 1H, J = 23.4 Hz), 3.64-3.50 (m, 3H), 3.49-3.35 (m, 4H), 2.99 (s, 3H), 2.89 (q, 1H, J = 7.2 Hz),1.83- 1.77 (m, 2H), 1.49 (d, 3H, J = 6.1 Hz), 1.32 (d, 6H, J = 6.8 Hz),1.11 (s, 6H) 1-{[(3R,4S)-3- fluoro-1-[4- ({8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)-2,7-naph- thyridin-3- yl}amino) pyrimidin-2-yl] piperidin-4-yl]oxy}-2-methyl- propan-2-ol 260

616 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.12 (s, 1H), 9.04 (s, 1H), 8.52(s, 1H), 8.05 (d, 1H, J = 5.6 Hz), 8.00 (s, 1H), 6.51 (d, 1H, J = 5.6Hz), 5.04-4.79 (m, 2H), 4.62 (dd, 1H, J = 14.0, 7.5 Hz), 4.55 (p, 1H, J= 5.8 Hz), 4.41-4.37 (m, 1H), 4.34 (s, 1H), 3.98 (t, 1H, J = 7.3 Hz),3.83- 3.68 (m, 1H), 3.64-3.50 (m, 3H), 3.49-3.34 (m, 4H), 2.99 (s, 3H),2.90 (p, 1H, J = 7.1 Hz), 1.83-1.77 (m, 2H), 1.49 (d, 3H, J = 6.1 Hz),1.32 (dd, 6H, J = 8.4, 6.8 Hz), 1.11 (s, 6H) 1-{[(3S,4R)-3- fluoro-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)-2,7-naph- thyridin-3- yl}amino) pyrimidin-2-yl]piperidin-4-yl] oxy}-2-methyl- propan-2-ol 261

557 ¹H NMR (400 MHz, DMSO-d₆) δ 9.85 (s, 1H), 9.03 (s, 1H), 8.59 (s,1H), 7.98 (d, J = 5.7 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 6.46 (d, J =5.7 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 4.92 (d, J = 49.3 Hz, 1H), 4.70(s, 1H), 4.46 (d, J = 13.0 Hz, 1H), 4.37 (t, J = 7.7 Hz, 2H), 3.94 (t, J= 6.9 Hz, 2H), 3.67-3.38 (m, 4H), 3.35 (s, 2H), 3.32-3.22 (m, 4H), 3.10(q, J = 7.4 Hz, 2H), 1.86- 1.64 (m, 2H), 1.34-1.14 (m, 9H). 8-{3-[(ethanesulfonyl) methyl]azetidin- 1-yl}-N-{2- [(3S,4R)-3- fluoro-4-methoxy- piperidin-1-yl] pyrimidin-4-yl}- 5-(propan-2- yl)isoquinolin-3-amine 262

557 ¹H NMR (400 MHz, DMSO-d₆) δ 9.87 (s, 1H), 9.04 (s, 1H), 8.61 (s,1H), 8.00 (d, J = 5.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.48 (d, J =5.7 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 4.93 (d, J = 49.5 Hz, 1H),4.79-4.67 (m, 1H), 4.48 (d, J = 13.5 Hz, 1H), 4.38 (t, J = 7.6 Hz, 2H),3.96 (t, J = 6.9 Hz, 2H), 3.67- 3.41 (m, 4H), 3.37 (s, 2H), 3.32-3.23(m, 4H), 3.11 (q, J = 7.4 Hz, 2H), 1.92- 1.62 (m, 2H), 1.37-1.15 (m,9H). 8-{3- [(ethanesulfonyl) methyl]azetidin- 1-yl}-N-{2- [(3R,4S)-3-fluoro-4- methoxy- piperidin-1-yl] pyrimidin-4-yl}- 5-(propan-2-yl)isoquinolin-3- amine 263

542 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 9.05 (s, 1H), 8.67 (s,1H), 8.00 (d, J = 5.6 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 6.56 (d, J =8.0 Hz, 1H), 6.43 (d, J = 5.7 Hz, 1H), 4.66 (t, J = 7.5 Hz, 1H),4.35-4.11 (m, 3H), 3.73- 3.34 (m, 7H), 2.89 (q, J = 7.2 Hz, 1H), 1.96(d, J = 27.6 Hz, 2H), 1.52-1.37 (m, 5H), 1.32-1.16 (m, 10H), 0.85 (dt, J= 9.3, 6.7 Hz, 3H) 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-N-{2-[4- (²H3)methoxy- piperidin-1-yl]pyrimidin-4-yl}- 5-(propan-2- yl)isoquinolin- 3-amine 264

547 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.06 (s, 1H), 8.53 (s,1H), 8.08 (d, J = 5.5 Hz, 1H), 8.02 (s, 1H), 6.56 (d, J = 5.7 Hz, 1H),4.97 (d, J = 49.7 Hz, 1H), 4.74 (s, 1H), 4.66- 4.51 (m, 2H), 4.49 (d, J= 13.6 Hz, 1H), 4.25 (dd, J = 8.6, 6.2 Hz, 2H), 3.69-3.43 (m, 4H), 3.04(s, 3H), 1.92-1.64 (m, 2H), 1.35 (dd, J = 6.8, 4.2 Hz, 6H).N-{2-[(3S,4R)- 3-fluoro-4- (²H3)methoxy- piperidin-1-yl]pyrimidin-4-yl}- 8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)-2,7-naph- thyridin-3-amine 265

547 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.15 (s, 1H), 8.75 (s,1H), 8.06 (dd, J = 5.7, 1.9 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6.50 (d,J = 5.9 Hz, 1H), 4.97 (d, J = 49.3 Hz, 1H), 4.76 (s, 1H), 4.51 (t, J =7.8 Hz, 3H), 4.10 (t, J = 6.9 Hz, 2H), 3.78-3.47 (m, 4H), 3.04 (d, J =2.1 Hz, 3H), 1.82 (d, J = 23.3 Hz, 2H), 1.34 (d, J = 7.1 Hz, 6H)N-{2-[(3S,4R)- 3-fluoro-4- (²H3)methoxy- piperidin-1-yl]pyrimidin-4-yl}- 8-[3-(methane- sulfonylmethyl) azetidin-1-yl]-5-(propan-2-yl)- 2,6-naph- thyridin-3- amine 266

538 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.09 (s, 1H), 9.03 (s, 1H), 8.68(s, 1H), 8.01 (d, 2H, J = 10.0 Hz), 6.56 (s, 1H), 4.85 (t, 1H, J = 8.0Hz), 4.54 (p, 1H, J = 6.1 Hz), 4.32-4.15 (m, 3H), 3.98 (t, 1H, J = 7.3Hz), 3.84 (t, 1H, J = 6.8 Hz), 3.75 (td, 1H, J = 10.5, 6.0 Hz),3.60-3.47 (m, 3H), 3.44 (t, 1H, J = 8.5 Hz), 2.99 (s, 3H), 2.88 (p, 1H,J = 7.2 Hz), 2.73-2.53 (m, 1H), 2.09 (dd, 1H, V; Peak 2 N-{2-[(3aR,6aS)- hexahydro-1H- furo[3,4-b] pyrrol-1-yl] pyrimidin-4-yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-amine or N-{2- [(3aS,6aR)-hexahydro-1H-

J = 11.2, 5.8 Hz), 1.91 (p, 1H, J = 10.5 Hz), 1.49 (d, 3H, J = 6.1 Hz),1.31 (dd, 6H, J = 6.8, 3.3 Hz) furo[3,4-b] pyrrol-1-yl] pyrimidin-4-yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-amine 267

538 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.14 (s, 1H), 9.13 (s, 1H), 8.90(s, 1H), 8.01 (d, 1H, J = 5.7 Hz), 7.73 (s, 1H), 6.51 (s, 1H), 4.74 (t,1H, J = 7.5 Hz), 4.41-4.13 (m, 4H), 3.90-3.66 (m, 4H), 3.62- 3.42 (m,4H), 3.01 (s, 3H), 2.93 (q, 1H, J = 7.2 Hz), 2.77-2.59 (m, 1H), 2.14-1.86 (m, 2H), 1.48 (d, 3H, J = 6.0 Hz), 1.30 (dd, 6H, J = 6.7, 3.4 Hz)V; Peak 2 N-(2- ((3aR,6aS)- hexahydro-1H- furo[3,4-b] pyrrol-1-yl)pyrimidin-4-yl)- 5-isopropyl-8- ((2R,3S)-2- methyl-3- ((methylsulfonyl)methyl)azetidin- 1-yl)-2,6-naph- thyridin-3-amine or N-(2- ((3aS,6aR)-hexahydro-1H-

furo[3,4-b] pyrrol-1-yl) pyrimidin-4-yl)- 5-isopropyl-8- ((2R,3S)-2-methyl-3- ((methylsulfonyl) methyl)azetidin- 1-yl)-2,6-naph-thyridin-3-amine 268

543 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.03 (s, 1H), 8.63(s, 1H), 7.98 (d, 1H, J = 5.7 Hz), 7.40 (d, 1H, J = 7.9 Hz), 6.54 (d,1H, J = 8.0 Hz), 6.45 (d, 1H, J = 5.7 Hz), 5.21 (d, 1H, J = 5.4 Hz),4.83 (d, 1H, J = 50.3 Hz), 4.64 (t, 1H, J = 7.5 Hz), 4.25-4.08 (m, 3H),3.77-3.39 (m, 8H), 2.98 (s, 3H), 2.87 (q, 1H, J = 7.3 Hz), 2.09-1.66 (m,2H), 1.40 (d, 3H, J = 5.9 Hz), 1.28 (d, 6H, J = 6.6 Hz) W; Peak 1(3R,4S)-4- fluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino)pyrimidin-2-yl] piperidin-3-ol or (3S,4R)-4- fluoro-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-

methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl] piperidin-3-ol 269

543 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.90 (s, 1H), 9.03 (s, 1H), 8.63(s, 1H), 7.98 (d, 1H, J = 5.7 Hz), 7.40 (d, 1H, J = 8.0 Hz), 6.54 (d,1H, J = 8.2 Hz), 6.44 (d, 1H, J = 5.7 Hz), 5.20 (d, 1H, J = 5.4 Hz),4.83 (d, 1H, J = 51.0 Hz), 4.64 (t, 1H, J = 7.5 Hz), 4.26-4.12 (m, 3H),3.74-3.40 (m, 8H), 2.98 (s, 3H), 2.93- 2.82 (m, 1H), 2.02-1.62 (m, 2H),1.40 (d, 3H, J = 6.0 Hz), 1.28 (dd, 6H, J = 6.8, 3.6 Hz) W; Peak 1(3S,4R)-4- fluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl] piperidin-3-ol or (3R,4S)-4- fluoro-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-

methylazetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino)pyrimidin-2-yl] piperidin-3-ol 270

543 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.05 (s, 1H), 8.87(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.2 Hz), 6.44 (d, 1H, J = 5.7 Hz), 5.32 (s, 1H), 4.66 (t, 1H, J= 7.5 Hz), 4.24- 4.14 (m, 1H), 3.88-3.44 (m, 10H), 3.00 (s, 3H),2.96-2.85 (m, 1H), 2.36-2.14 (m, 2H), 1.43 (d, 3H, J = 6.1 Hz), 1.30(dd, 6H, J = 6.8, 2.5 Hz) F; Peak 1 [(3R)-3-fluoro- 1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]pyrrolidin-3-yl] methanol or [(3S)-3-fluoro- 1-[4-({8- [(2R,3S)-3-

(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl] pyrrolidin-3-yl] methanol271

543 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.05 (s, 1H), 8.86(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.44 (d, 1H, J = 5.7 Hz), 5.35-5.29 (m, 1H), 4.66 (t,1H, J = 7.5 Hz), 4.24-4.14 (m, 1H), 3.93- 3.41 (m, 10H), 3.00 (s, 3H),2.89 (q, 1H, J = 8.2, 7.6 Hz), 2.33-2.15 (m, 2H), 1.43 (d, 3H, J = 6.0Hz), 1.34-1.21 (m, 6H) F; Peak 2 [(3S)-3-fluoro- 1-[4-({8- [(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl] pyrrolidin-3-yl] methanol or[(3R)-3-fluoro- 1-[4-({8- [(2R,3S)-3-

(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl] pyrrolidin-3-yl] methanol272

556 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.03 (s, 1H), 8.60(s, 1H), 7.98 (d, 1H, J = 5.7 Hz), 7.40 (d, 1H, J = 8.0 Hz), 6.46 (d,1H, J = 5.7 Hz), 6.38 (d, 1H, J = 8.1 Hz), 4.93 (d, 1H, J = 49.8 Hz),4.74 (d, 1H, J = 13.5 Hz), 4.47 (d, 1H, J = 13.3 Hz), 4.35 (q, 2H, J =7.5 Hz), 3.95 (dt, 2H, J = 13.2, 6.9 Hz), 3.70-3.33 (m, 10H), 2.99 (q,2H, J = 7.3 Hz), 1.86-1.63 (m, 2H), 1.33-1.16 (m, 9H) U; Peak 1(R)-ethyl({1- [3-({2-[(3S,4R)- 3-fluoro-4- methoxy- piperidin-1-yl]pyrimidin-4-yl} amino)-5- (propan-2-yl) isoquinolin-8- yl]azetidin-3-yl}methyl) imino-λ⁶- sulfanone or (S)-ethyl({1- [3-({2- [(3S,4R)-3-fluoro-4- methoxy-

piperidin-1-yl] pyrimidin-4-yl} amino)-5- (propan-2-yl) isoquinolin-8-yl]azetidin-3- yl}methyl) imino-λ⁶- sulfanone 273

556 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.88 (s, 1H), 9.03 (s, 1H), 8.60(s, 1H), 7.98 (d, 1H, J = 5.7 Hz), 7.40 (d, 1H, J = 8.0 Hz), 6.46 (d,1H, J = 5.7 Hz), 6.38 (d, 1H, J = 8.0 Hz), 4.92 (d, 1H, J = 50.3 Hz),4.81-4.59 (m, 1H), 4.48 (d, 1H, J = 13.3 Hz), 4.35 (q, 2H, J = 7.3 Hz),3.95 (dt, 2H, J = 13.2, 6.8 Hz), 3.74-3.55 (m, 10H), 2.98 (t, 2H, J =7.4 Hz), 1.89-1.59 (m, 2H), 1.34- 1.09 (m, 9H) U; Peak 2 (S)-ethyl({1-[3-({2- [(3S,4R)-3- fluoro-4- methoxy- piperidin-1-yl] pyrimidin-4-yl}amino)-5- (propan-2-yl) isoquinolin-8- yl]azetidin-3- yl}methyl)imino-λ⁶- sulfanone or (R)-ethyl({1- [3-({2- [(3S,4R)-3- fluoro-4-

methoxy- piperidin-1-yl] pyrimidin-4- yl}amino)-5- (propan-2-yl)isoquinolin-8- yl]azetidin-3- yl}methyl) imino-λ⁶- sulfanone 274

556 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.03 (s, 1H), 8.60(s, 1H), 7.98 (d, 1H, J = 5.7 Hz), 7.40 (d, 1H, J = 8.0 Hz), 6.46 (d,1H, J = 5.7 Hz), 6.38 (d, 1H, J = 8.1 Hz), 4.92 (d, 1H, J = 49.3 Hz),4.72 (s, 1H), 4.47 (d, 1H, J = 13.2 Hz), 4.35 (q, 2H, J = 7.4 Hz), 3.95(dt, 2H, J = 12.8, 6.7 Hz), 3.74-3.38 (m, 10H), 3.00 (q, 2H, J = 7.4Hz), 1.83-1.67 (m, 2H), 1.33-1.16 (m, 9H) U; Peak 1 (R)-methyl({1-[3-({2- [(3R,4S)-3- fluoro-4- methoxy- piperidin-1-yl] pyrimidin-4-yl}amino)-5- (propan-2-yl) isoquinolin-8- yl]azetidin-3- yl}methyl)imino-λ⁶- sulfanone or (S)-methyl({1- [3-({2- [(3R,4S)-3-

fluoro-4- methoxy- piperidin-1-yl] pyrimidin-4- yl}amino)-5-(propan-2-yl) isoquinolin-8- yl]azetidin-3- yl}methyl) imino-λ⁶-sulfanone 275

556 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.03 (s, 1H), 8.60(s, 1H), 7.98 (d, 1H, J = 5.7 Hz), 7.39 (d, 1H, J = 8.0 Hz), 6.46 (d,1H, J = 5.7 Hz), 6.38 (d, 1H, J = 8.1 Hz), 5.06-4.79 (m, 1H), 4.72 (dt,1H, J = 13.6, 7.6 Hz), 4.47 (d, 1H, J = 13.5 Hz), 4.35 (td, 2H, J = 7.6,4.6 Hz), 3.95 (dt, 2H, J = 11.7, 6.8 Hz), 3.66-3.41 (m, 7H), 3.30-3.16(m, 3H), 3.00 (q, 2H, J = 7.4 Hz), 1.87-1.67 (m, 2H), 1.34-1.16 (m, 9H)U; Peak 2 (S)-ethyl({1- [3-({2- [(3R,4S)-3- fluoro-4- methoxy-piperidin-1-yl] pyrimidin-4- yl}amino)-5- (propan-2-yl) isoquinolin-8-yl]azetidin-3- yl}methyl) imino-λ⁶- sulfanone or (R)-ethyl({1- [3-({2-[(3R,4S)-3-

fluoro-4- methoxy- piperidin-1-yl] pyrimidin-4- yl}amino)-5-(propan-2-yl) isoquinolin-8- yl]azetidin-3- yl}methyl) imino-λ⁶-sulfanone 276

557 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.90 (s, 1H), 9.02 (s, 1H), 8.62(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.39 (d, 1H, J = 8.0 Hz), 6.46 (d,1H, J = 5.7 Hz), 6.39 (d, 1H, J = 8.0 Hz), 4.84 (s, 1H), 4.38 (q, 3H, J= 8.1 Hz), 4.30-4.12 (m, 2H), 3.94 (t, 2H, J = 6.9 Hz), 3.62-3.42 (m,5H), 3.10 (q, 2H, J = 7.5 Hz), 1.75-1.48 (m, 2H), 1.32-1.17 (m, 12H)(3S,4R)-1- {4-[(8-{3- [(ethanesulfonyl) methyl]azetidin- 1-yl}-5-(propan-2-yl) isoquinolin-3- yl)amino] pyrimidin-2-yl}- 3-fluoro-4-methyl- piperidin-4-ol 277

557 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.03 (s, 1H), 8.62(s, 1H), 7.99 (d, 1H, J = 5.7 Hz), 7.39 (d, 1H, J = 8.0 Hz), 6.46 (d,1H, J = 5.7 Hz), 6.39 (d, 1H, J = 8.1 Hz), 4.84 (s, 1H), 4.38 (q, 3H, J= 8.1 Hz), 4.27-4.09 (m, 2H), 3.94 (t, 2H, J = 6.9 Hz), 3.68-3.40 (m,5H), 3.29-3.20 (m, 1H), 3.10 (q, 2H, J = 7.4 Hz), 1.71-1.42 (m, 2H),1.32- 1.17 (m, 12H) OO; Peak 2 (3R,4S)-1- {4-[(8-{3- [(ethanesulfonyl)methyl]azetidin- 1-yl}-5- (propan-2-yl) isoquinolin-3- yl)amino]pyrimidin-2-yl}- 3-fluoro-4- methyl- piperidin-4-ol 278

557 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.98 (s, 1H), 9.06 (s, 1H), 8.63(s, 1H), 8.02 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.50 (d, 1H, J = 5.8 Hz), 4.72-4.37 (m, 3H), 4.20 (t,2H, J = 6.3 Hz), 3.69-3.45 (m, 7H), 3.41 (s, 3H), 3.00 (s, 3H),2.96-2.85 (m, 1H), 2.09-2.03 (m, 1H), 1.57-1.47 (m, 1H), 1.43 (d, 3H, J= 6.0 Hz), 1.30 (t, 6H, J = 6.2 Hz) X; Peak 1 N-{2-[(3R,4R)- 3-fluoro-4-methoxy- piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- amine or N-{2- [(3S,4S)-3- fluoro-4- methoxy-

piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine279

557 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.98 (s, 1H), 9.06 (s, 1H), 8.63(s, 1H), 8.02 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.50 (d, 1H, J = 5.6 Hz), 4.72-4.38 (m, 3H), 4.29-4.15(m, 2H), 3.70-3.43 (m, 7H), 3.41 (s, 3H), 3.00 (s, 3H), 2.89 (q, 1H, J =7.0 Hz), 2.08-2.02 (m, 1H), 1.52-1.46 (m, 1H), 1.43 (d, 3H, J = 6.0 Hz),1.30 (dd, 6H, J = 6.8, 3.0 Hz) X; Peak 2 N-{2-[(3S,4S)- 3-fluoro-4-methoxy- piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- amine or N-{2- [(3R,4R)-3- fluoro-4- methoxy-

piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine280

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.54 (s, 1H), 9.11 (s, 1H), 8.69(s, 1H), 8.50 (s, 1H), 7.46 (d, 1H, J = 8.0 Hz), 6.47 (d, 1H, J = 8.1Hz), 4.99 (d, 1H, J = 49.0 Hz), 4.75 (s, 1H), 4.58-4.46 (m, 1H), 4.41(t, 2H, J = 7.7 Hz), 3.98 (t, 2H, J = 6.9 Hz), 3.71-3.43 (m, 5H), 3.37(s, 3H), 3.33-3.24 (m, 2H), 3.12 (q, 2H, J = 7.4 Hz), 1.92-1.62 (m, 2H),1.30 (dd, 6H, J = 6.7, 3.7 Hz), 1.24 (t, 3H, J = 7.4 Hz) 8-{3-[(ethanesulfonyl) methyl]azetidin- 1-yl}-N- {3-[(3S,4R)-3- fluoro-4-methoxy- piperidin-1-yl]- 1,2,4-triazin-5- yl}-5-(propan-2-yl)isoquinolin- 3-amine 281

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.53 (s, 1H), 9.10 (s, 1H), 8.69(s, 1H), 8.49 (s, 1H), 7.46 (d, 1H, J = 8.0 Hz), 6.47 (d, 1H, J = 8.1Hz), 4.99 (d, 1H, J = 50.3 Hz), 4.79- 4.73 (m, 1H), 4.56-4.46 (m, 1H),4.40 (t, 2H, J = 7.6 Hz), 3.98 (t, 2H, J = 6.9 Hz), 3.70-3.43 (m, 8H),3.37-3.20 (m, 2H), 3.12 (q, 2H, J = 7.4 Hz), 1.88-1.66 (m, 2H), 1.35-1.18 (m, 9H) 8-{3- [(ethanesulfonyl) methyl]azetidin- 1-yl}-N-{3-[(3R,4S)-3- fluoro-4- methoxy- piperidin-1-yl]- 1,2,4-triazin-5-yl}-5-(propan- 2-yl)isoquinolin- 3-amine 282

560 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.06 (s, 1H), 8.65(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.47 (d, 1H, J = 5.7 Hz), 4.95 (d, 1H, J = 49.9 Hz),4.77-4.61 (m, 2H), 4.49 (d, 1H, J = 13.6 Hz), 4.20 (t, 1H, J = 6.3 Hz),3.74-3.38 (m, 6H), 3.32-3.21 (m, 1H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.2Hz), 1.84- 1.70 (m, 2H), 1.43 (d, 3H, J = 6.0 Hz), 1.31 (dd, 6H, J =6.9, 1.7 Hz) Z; Peak 1 N-{2-[(3S,4R)- 3-fluoro-4- (²H3)methoxy-piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine283

560 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.06 (s, 1H), 8.65(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.47 (d, 1H, J = 5.7 Hz), 4.95 (d, 1H, J = 49.4 Hz),4.78-4.61 (m, 2H), 4.49 (d, 1H, J = 13.3 Hz), 4.20 (t, 1H, J = 6.3 Hz),3.70-3.38 (m, 6H), 3.33-3.21 (m, 1H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.3Hz), 1.85-1.63 (m, 2H), 1.43 (d, 3H, J = 6.0 Hz), 1.31 (dd, 6H, J = 6.8,4.8 Hz) Z; Peak 2 N-{2-[(3R,4S)- 3-fluoro-4- (²H3)methoxy-piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine284

561 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.14 (s, 1H), 9.05 (s, 1H), 8.52(s, 1H), 8.05 (d, 1H, J = 5.6 Hz), 8.01 (s, 1H), 6.52 (d, 1H, J = 5.7Hz), 5.08-4.81 (m, 2H), 4.75-4.69 (m, 1H), 4.61-4.40 (m, 2H), 3.99 (t,1H, J = 7.3 Hz), 3.69-3.42 (m, 5H), 2.99 (s, 3H), 2.96- 2.83 (m, 1H),1.84-1.72 (m, 2H), 1.50 (d, 3H, J = 6.1 Hz), 1.33 (t, 6H, J = 6.7 Hz) Z;Peak 1 N-{2-[(3S,4R)- 3-fluoro-4- (²H3)methoxy- piperidin-1-yl]pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-amine 285

561 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.14 (s, 1H), 9.05 (s, 1H), 8.52(s, 1H), 8.05 (d, 1H, J = 5.6 Hz), 8.01 (s, 1H), 6.52 (d, 1H, J = 5.7Hz), 5.09-4.81 (m, 2H), 4.76-4.36 (m, 3H), 3.98 (t, 1H, J = 7.3 Hz),3.67-3.36 (m, 5H), 2.99 (s, 3H), 2.89 (d, 1H, J = 7.1 Hz), 1.85- 1.79(m, 2H), 1.50 (d, 3H, J = 6.1 Hz), 1.33 (d, 6H, J = 6.8 Hz) Z; Peak 2N-{2-[(3R,4S)- 3-fluoro-4- (²H3)methoxy- piperidin-1-yl]pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-amine 286

564 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.99 (s, 1H), 9.06 (s, 1H), 8.57(s, 1H), 8.03 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.2 Hz), 6.55 (d,1H, J = 5.9 Hz), 6.43 (d, 1H, J = 8.0 Hz), 4.45-4.28 (m, 3H), 4.16-3.90(m, 4H), 3.88-3.69 (m, 2H), 3.64- 3.42 (m, 4H), 3.02 (s, 3H), 2.00-1.63(m, 2H), 1.30 (d, 6H, J = 6.7 Hz) Z; Peak 1 N-{2-[(4S)- 3,3-difluoro-4-(²H3)methoxy- piperidin-1-yl] pyrimidin-4-yl}- 8-[3-(methane-sulfonylmethyl) azetidin-1-yl]- 5-(propan-2- yl)isoquinolin- 3-amine orN- {2-[(4R)- 3,3-difluoro-4- (²H3)methoxy- piperidin-1-yl]

pyrimidin-4-yl}- 8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine 287

564 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.99 (s, 1H), 9.06 (s, 1H), 8.57(s, 1H), 8.03 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.55 (d,1H, J = 5.8 Hz), 6.43 (d, 1H, J = 8.1 Hz), 4.51-4.19 (m, 3H), 4.17-3.89(m, 4H), 3.79 (d, 2H, J = 16.4 Hz), 3.64-3.31 (m, 4H), 2.11-1.58 (m,2H), 1.30 (d, 6H, J = 6.7 Hz) Z; Peak 2 N-{2-[(4R)- 3,3-difluoro-4-(²H3)methoxy- piperidin-1-yl] pyrimidin-4- yl}-8-[3- (methanesulfonyl-methyl)azetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine or N-{2-[(4S)-3,3- difluoro-4- (²H3)methoxy- piperidin-1-yl]

pyrimidin-4- yl}-8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- amine 288

572 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.57 (s, 1H), 9.11 (s, 1H), 8.70(s, 1H), 8.48 (s, 1H), 7.47 (d, 1H, J = 8.0 Hz), 6.62 (d, 1H, J = 8.1Hz), 4.99 (d, 1H, J = 49.6 Hz), 4.79- 4.62 (m, 2H), 4.51 (d, 1H, J =13.4 Hz), 4.21 (t, 1H, J = 6.3 Hz), 3.70-3.43 (m, 9H), 3.37-3.22 (m,1H), 3.09 (q, 2H, J = 7.4 Hz), 2.89 (q, 1H, J = 7.2 Hz), 1.88-1.65 (m,2H), 1.42 (d, 3H, J = 6.0 Hz), 1.35- 1.17 (m, 9H) 8-[(2R,3S)-3-[(ethanesulfonyl) methyl]-2- methylazetidin- 1-yl]-N-{3- [(3S,4R)-3-fluoro-4- methoxy- piperidin-1- yl]-1,2,4-triazin- 5-yl}-5-(propan-2-yl)isoquinolin- 3-amine 289

572 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.57 (s, 1H), 9.11 (s, 1H), 8.70(s, 1H), 8.49 (s, 1H), 7.48 (d, 1H, J = 8.0 Hz), 6.63 (d, 1H, J = 8.1Hz), 5.00 (d, 1H, J = 49.3 Hz), 4.79- 4.63 (m, 2H), 4.52 (d, 1H, J =13.7 Hz), 4.21 (t, 1H, J = 6.2 Hz), 3.71-3.46 (m, 7H), 3.40-3.30 (m,3H), 3.09 (q, 2H, J = 7.5 Hz), 2.89 (q, 1H, J = 7.2 Hz), 1.89-1.64 (m,2H), 1.43 (d, 3H, J = 6.0 Hz), 1.36- 1.17 (m, 9H) 8-[(2R,3S)-3-[(ethanesulfonyl) methyl]-2- methylazetidin- 1-yl]-N-{3- [(3R,4S)-3-fluoro-4- methoxy- piperidin-1-yl]- 1,2,4-triazin-5- yl}-5-(propan-2-yl)isoquinolin- 3-amine 290

573 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.91 (s, 1H), 9.05 (s, 1H), 8.00(d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.48 (d, 1H, J = 5.7 Hz),6.42 (d, 1H, J = 8.0 Hz), 5.08-4.62 (m, 3H), 4.54 (d, 1H, J = 13.1 Hz),4.39 (t, 2H, J = 7.7 Hz), 3.97 (t, 2H, J = 6.9 Hz), 3.74 (d, 1H, J =24.5 Hz), 3.65-3.45 (m, 8H), 3.22-3.17 (m, 2H), 3.02 (s, 3H), 1.91-1.68(m, 2H), 1.31 (dd, 6H, J = 6.8, 3.2 Hz) 2-{[(3R,4S)-3- fluoro-1-[4-({8-[3- (methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan-2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl] piperidin-4-yl]oxy}ethan-1-ol 291

577 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.96 (s, 1H), 9.05 (s, 1H), 8.52(s, 1H), 8.02 (d, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 8.1 Hz), 6.57 (d,1H, J = 5.7 Hz), 6.42 (d, 1H, J = 8.1 Hz), 5.31 (d, 1H, J = 5.9 Hz),4.82-4.77 (m, 1H), 4.56-4.48 (m, 1H), 4.38 (td, 2H, J = 7.5, 2.6 Hz),3.96 (td, 2H, J = 7.1, 2.8 Hz), 3.71 (dd, 2H, J = 13.1, 8.4 Hz),3.64-3.55 (m, 5H), 3.55-3.48 (m, 2H), 3.33-3.29 (m, 1H), 3.20-3.13 (m,1H), 3.01 (s, 3H), 1.28 (dd, 6H, J = 9.8, 6.7 Hz) BB, Peak 1(3R,4R)-5,5- difluoro-1-[4- ({8-[3- (methanesulfonyl- methyl)azetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]-4-methoxy- piperidin-3-ol or (3S,4S)-5,5- difluoro-1-[4- ({8-[3-(methanesulfonyl- methyl)azetidin- 1-yl]-5-(propan-

2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-ol292

587 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.03 (s, 1H), 8.61(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.40 (d, 1H, J = 8.0 Hz), 6.46 (d,1H, J = 5.7 Hz), 6.39 (d, 1H, J = 8.1 Hz), 5.05-4.70 (m, 2H), 4.63 (t,1H, J = 5.2 Hz), 4.52 (d, 1H, J = 13.5 Hz), 4.37 (t, 2H, J = 7.6 Hz),3.94 (t, 2H, J = 6.9 Hz), 3.83-3.66 (m, 1H), 3.62-3.37 (m, 9H), 3.25 (d,1H, J = 7.9 Hz), 3.10 (q, 2H, J = 7.4 Hz), 1.86-1.63 (m, 2H), 1.37-1.12(m, 9H) 2-{[(3S,4R)-1- {4-[(8-{3- [(ethanesulfonyl) methyl]azetidin-1-yl}-5-(propan- 2-yl)isoquinolin- 3-yl)amino] pyrimidin-2-yl}-3-fluoro- piperidin-4-yl] oxy}ethan-1-ol 293

587 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.89 (s, 1H), 9.03 (s, 1H), 8.61(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.40 (d, 1H, J = 8.1 Hz), 6.45 (d,1H, J = 5.7 Hz), 6.39 (d, 1H, J = 8.1 Hz), 5.08-4.69 (m, 2H), 4.64 (d,1H, J = 5.3 Hz), 4.52 (d, 1H, J = 13.4 Hz), 4.37 (t, 2H, J = 7.6 Hz),3.94 (t, 2H, J = 6.9 Hz), 3.79-3.63 (m, 1H), 3.63-3.37 (m, 8H),3.29-3.17 (m, 1H), 3.10 (q, 2H, J = 7.4 Hz), 1.92-1.60 (m, 2H),1.35-1.08 (m, 9H) 2-{[(3R,4S)-1- {4-[(8-{3- [(ethanesulfonyl)methyl]azetidin- 1-yl}-5-(propan- 2-yl)isoquinolin- 3-yl)amino]pyrimidin-2-yl}- 3-fluoro- piperidin-4-yl] oxy}ethan-1-ol 294

591 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.97 (s, 1H), 9.05 (s, 1H), 8.52(s, 1H), 8.02 (d, 1H, J = 5.7 Hz), 7.41 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 5.5 Hz), 6.41 (d, 1H, J = 8.1 Hz), 5.31 (d, 1H, J = 5.8 Hz),4.80 (s, 1H), 4.56- 4.48 (m, 1H), 4.43-4.34 (m, 2H), 3.96 (td, 2H, J =7.0, 2.7 Hz), 3.82-3.66 (m, 2H), 3.64-3.51 (m, 6H), 3.54-3.48 (m, 1H),3.30-3.23 (m, 1H), 3.22-3.04 (m, 3H), 1.33- 1.20 (m, 9H) BB, Peak 1(3R,4R)-1-{4- [(8-{3- [(ethanesulfonyl) methyl]azetidin-1-yl}-5-(propan- 2-yl)isoquinolin- 3-yl)amino] pyrimidin-2-yl}-5,5-difluoro-4- methoxy- piperidin-3-ol or (3S,4S)-1-{4- [(8-{3-[(ethanesulfonyl) methyl]azetidin- 1-yl}-5-(propan- 2-yl)isoquinolin-3-yl)amino]

pyrimidin-2-yl}- 5,5-difluoro-4- methoxy- piperidin-3-ol 295

599 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.93 (s, 1H), 9.06 (s, 1H), 8.64(s, 1H), 7.99 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.46 (d, 1H, J = 5.8 Hz), 4.67 (t, 1H, J = 7.6 Hz),4.55-4.49 (m, 1H), 4.19 (t, 1H, J = 6.3 Hz), 4.12-4.06 (m, 2H),4.03-3.97 (m, 1H), 3.83-3.39 (m, 12H), 3.36 (s, 3H), 3.00 (s, 3H), 2.89(q, 1H, J = 7.0 Y; Peak 1 2-{[(3R,4S)-1- [4-({8- [(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methoxy- piperidin-3-yl]oxy}ethan-1-ol

Hz), 1.89-1.58 (m, 2H), 1.43 (d, 3H, J = 6.0 Hz), 1.31 (d, 6H, J = 6.7Hz) or 2-{[(3S,4R)- 1-[4-({8- [(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- yl}amino)pyrimidin-2-yl]- 4-methoxy- piperidin-3-yl] oxy}ethan-1-ol 296

599 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.90 (s, 1H), 9.05 (s, 1H), 8.65(s, 1H), 7.99 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.56 (d,1H, J = 8.1 Hz), 6.45 (d, 1H, J = 5.6 Hz), 4.66 (t, 1H, J = 7.5 Hz),4.54-4.48 (m, 1H), 4.19 (t, 1H, J = 6.3 Hz), 4.08-4.02 (m, 2H),3.73-3.38 (m, 12H), 3.36 (s, 3H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.1Hz), 1.88-1.58 (m, 2H), 1.43 Y; Peak 2 2-{[(3S,4R)-1- [4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methoxy-piperidin-3-yl] oxy}ethan-1-ol

(d, 3H, J = 6.0 Hz), 1.31 (d, 6H, J = 6.6 Hz) or 2-{[(3R,4S)- 1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]- 4-methoxy-piperidin-3-yl] oxy}ethan-1-ol 297

600 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.94 (s, 1H), 9.06 (s, 1H), 8.65(s, 1H), 8.00 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.1 Hz), 6.47 (d, 1H, J = 5.7 Hz), 4.93 (d, 1H, J = 49.9 Hz),4.77-4.61 (m, 2H), 4.49 (d, 1H, J = 13.3 Hz), 4.20 (t, 1H, J = 6.3 Hz),3.82-3.43 (m, 8H), 3.00 (s, 3H), 2.89 (d, 1H, J = 7.5 Hz), 2.70 (t, 2H,J = 5.7 Hz), 2.34 (s, 3H), 1.84-1.78 (m, 2H), 1.43 (d, 3H, J = 6.0 Hz),1.39-1.21 (m, 6H) N-{2-[(3R,4S)- 3-fluoro-4-[2- (methylamino) ethoxy]piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine298

602 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.17 (s, 1H), 9.14 (s, 1H), 8.76(s, 1H), 8.04 (d, 1H, J = 5.6 Hz), 7.73 (s, 1H), 6.46 (d, 1H, J = 5.7Hz), 4.95 (d, 1H, J = 49.8 Hz), 4.81-4.62 (m, 3H), 4.55 (d, 1H, J = 13.4Hz), 4.32 (t, 1H, J = 6.3 Hz), 3.83-3.67 (m, 3H), 3.64-3.49 (m, 7H),3.30-3.24 (m, 1H), 3.10 (q, 2H, J = 7.4 Hz), 2.92 (q, 1H, J = 7.4 Hz),1.86- 1.76 (m, 2H), 1.49 (d, 3H, J = 6.0 Hz), 1.32 (dd, 6H, J = 8.3, 6.7Hz), 1.24 (t, 2-{[(3S,4R)-1- [4-({8- [(2R,3S)-3- [(ethanesulfonyl)methyl]-2- methylazetidin- 1-yl]-5-(propan- 2-yl)-2,6-naph- thyridin-3-yl}amino) pyrimidin-2-yl]- 3-fluoro- piperidin-4-yl] oxy}ethan-1-ol 3H,J = 7.4 Hz) 299

602 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.17 (s, 1H), 9.13 (s, 1H), 8.76(s, 1H), 8.04 (d, 1H, J = 5.6 Hz), 7.73 (s, 1H), 6.46 (d, 1H, J = 5.7Hz), 4.95 (d, 1H, J = 50.6 Hz), 4.81-4.62 (m, 3H), 4.55 (d, 1H, J = 13.5Hz), 4.32 (t, 1H, J = 6.3 Hz), 3.83-3.67 (m, 3H), 3.64-3.51 (m, 7H),3.31-3.21 (m, 1H), 3.09 (q, 2H), 2.92 (q, 1H, J = 7.3 Hz), 1.86-1.80 (m,2H), 1.49 (d, 3H, J = 6.0 Hz), 1.38-1.18 (m, 9H) 2-{[(3R,4S)-1- [4-({8-[(2R,3S)-3- [(ethanesulfonyl) methyl]-2- methylazetidin-1-yl]-5-(propan- 2-yl)-2,6-naph- thyridin-3- yl}amino) pyrimidin-2-yl]-3-fluoro- piperidin-4-yl] oxy}ethan-1-ol 300

618 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.02 (s, 1H), 9.07 (s, 1H), 8.59(s, 1H), 8.03 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.62-6.50(m, 2H), 4.67 (t, 1H, J = 7.5 Hz), 4.42-3.83 (m, 5H), 3.83- 3.36 (m,8H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.1 Hz), 2.66 (td, 2H, J = 5.6, 1.5Hz), 2.31 (s, 3H), 1.99- 1.68 (m, 2H), 1.43 (d, 3H, G; Peak 1N-{2-[(4R)- 3,3-difluoro- 4-[2- (methylamino) ethoxy] piperidin-1-yl]pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3-

J = 6.0 Hz), 1.30 (dd, 6H, J = 6.7, 3.6 Hz) amine or N-{2- [(4S)-3,3-difluoro-4-[2- (methylamino) ethoxy] piperidin-1-yl] pyrimidin-4-yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- amine 301

618 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.02 (s, 1H), 9.07 (s, 1H), 8.59(s, 1H), 8.03 (d, 1H, J = 5.7 Hz), 7.44 (d, 1H, J = 8.0 Hz), 6.62-6.50(m, 2H), 4.67 (t, 1H, J = 7.5 Hz), 4.40-4.29 (m, 1H), 4.20 (t, 1H, J =6.2 Hz), 4.14- 3.98 (m, 2H), 3.95-3.89 (m, 1H), 3.81-3.42 (m, 8H), 3.00(s, 3H), 2.89 (q, 1H, J = 7.2 Hz), 2.72 G; Peak 2 N-{2-[(4S)-3,3-difluoro-4-[2- (methylamino) ethoxy] piperidin-1-yl] pyrimidin-4-yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine or N-

(t, 2H, J = 5.7 Hz), 2.34 (s, 3H), 2.00-1.69 (m, 2H), 1.43 (d, 3H, J =6.0 Hz), 1.30 (d, 6H, J = 6.7 Hz) {2-[(4R)-3,3- difluoro-4-[2-(methylamino) ethoxy]piperidin- 1-yl]pyrimidin- 4-yl}-8- [(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin- 1-yl]-5-(propan-2-yl)isoquinolin- 3-amine 302

619 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.02 (s, 1H), 9.07 (s, 1H), 8.59(s, 1H), 8.03 (d, 1H, J = 5.6 Hz), 7.44 (d, 1H, J = 8.0 Hz), 6.62-6.50(m, 2H), 4.68 (dt, 2H, J = 12.0, 6.4 Hz), 4.40 (d, 1H, J = 13.6 Hz),4.25-3.85 (m, 4H), 3.77-3.39 (m, 9H), 3.08 (t, 2H, J = 7.4 Hz), 2.89 (q,1H, J = 7.2 Hz), 2.01- 1.66 (m, 2H), 1.43 (d, 3H, J = 5.9 Hz), 1.34-1.18(m, G; Peak 1 2-{[(4R)-1-[4- ({8-[(2R,3S)-3- [(ethanesulfonyl)methyl]-2- methylazetidin- 1-yl]-5-(propan- 2-yl)isoquinolin-3-yl}amino) pyrimidin-2-yl]- 3,3-difluoro- piperidin-4-yl]oxy}ethan-1-ol or 2-{[(4S)-1- [4-({8-

9H) [(2R,3S)-3- [(ethanesulfonyl) methyl]-2- methylazetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]-3,3-difluoro- piperidin-4-yl] oxy}ethan-1-ol 303

619 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.02 (s, 1H), 9.07 (s, 1H), 8.59(s, 1H), 8.03 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.62-6.50(m, 2H), 4.75-4.61 (m, 2H), 4.44- 4.33 (m, 1H), 4.26-3.83 (m, 4H),3.81-3.41 (m, 9H), 3.10 (q, 2H, J = 7.4 Hz), 2.93-2.84 (m, 1H),2.01-1.67 (m, 2H), 1.43 (d, 3H, J = 5.9 Hz), 1.38- 1.18 (m, 9H) G; Peak2 2-{[(4S)-1-[4- ({8-[(2R,3S)-3- [(ethanesulfonyl) methyl]-2-methylazetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino)pyrimidin-2-yl]- 3,3-difluoro- piperidin-4-yl] oxy}ethan-1-ol or2-{[(4R)-1- [4-({8-

[(2R,3S)-3- [(ethanesulfonyl) methyl]-2- methylazetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-yl}amino) pyrimidin-2-yl]-3,3-difluoro- piperidin-4-yl] oxy}ethan-1-ol 304

632 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.02 (s, 1H), 9.07 (s, 1H), 8.59(s, 1H), 8.03 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.62-6.50(m, 2H), 4.67 (t, 1H, J = 7.5 Hz), 4.43-3.86 (m, 6H), 3.81- 3.44 (m,6H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.2 Hz), 2.51-2.43 (m, 1H), 2.20 (s,6H), 2.00-1.75 (m, 2H), 1.43 (d, 3H, G; Peak 1 N-{2-[(4R)-4-[2-(dimethyl- amino)ethoxy]- 3,3-difluoro- piperidin-1-yl]pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine or N-

J = 6.0 Hz), 1.30 (dd, 6H, J = 6.7, 3.4 Hz) {2-[(4S)-4-[2-(dimethylamino) ethoxy]-3,3- difluoro- piperidin-1-yl] pyrimidin-4-yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine 305

632 1H-NMR (300 MHz, 6d- DMSO) δ ppm 10.02 (s, 1H), 9.07 (s, 1H), 8.59(s, 1H), 8.03 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.62-6.50(m, 2H), 4.67 (t, 1H, J = 7.5 Hz), 4.46-4.27 (m, 1H), 4.20 (t, 1H, J =6.3 Hz), 4.12- 4.06 (m, 2H), 4.01-3.89 (m, 2H), 3.81-3.46 (m, 6H), 3.00(s, 3H), 2.89 (q, 1H, J = 7.2 Hz), 2.57 G; Peak 2 N-{2-[(4S)-4-[2-(dimethyl- amino)ethoxy]- 3,3-difluoro- piperidin-1-yl]pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine or N-

(t, 2H, J = 5.8 Hz), 2.26 (s, 6H), 2.01-1.68 (m, 2H), 1.43 (d, 3H, J =6.0 Hz), 1.30 (d, 6H, J = 6.7 Hz) {2-[(4R)-4-[2- (dimethylamino)ethoxy]-3,3- difluoro- piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- amine 306

556 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.61 (s, 1H), 8.07 (d, J =5.6 Hz, 1H), 7.46- 7.37 (m, 2H), 6.53 (d, J = 8.0 Hz, 1H), 6.16 (d, J =5.6 Hz, 1H), 5.22-5.08 (m, 1H), 5.03- 4.82 (m, 2H), 4.71-4.65 (m, 1H),4.29-4.22 (m, 1H), 3.69-3.56 (m, 2H), 3.41-3.19 (m, 3H), 3.17- 3.09 (m,1H), 3.08-3.01 (m, 1H), 2.96 (s, 3H), 2.83-2.70 (m, 1H), 2.54 (s, 3H),1.98-1.89 (m, E; Peak 2 N-{2-[(3R,4S)-3- fluoro-4- (methylamino)piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl-methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine orN-{2- [(3S,4R)-3- fluoro-4- (methylamino) piperidin-1-yl]

1H), 1.83-1.74 (m, 1H), 1.52 (d, J = 6.0 Hz, 3H), 1.39-1.34 (m, 6H).pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine 307

556 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.61 (s, 1H), 8.07 (d, J =5.6 Hz, 1H), 7.48 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 6.53 (d, J = 8.0Hz, 1H), 6.16 (d, J = 5.6 Hz, 1H), 5.22-5.12 (m, 1H), 5.03- 4.81 (m,2H), 4.70-4.64 (m, 1H), 4.29-4.22 (m, 1H), 3.68-3.57 (m, 2H), 3.43-3.27(m, 3H), 3.16- 3.09 (m, 1H), 3.07-3.01 (m, 1H), 2.96 (s, 3H), 2.83-2.71(m, 1H), 2.55 (s, 3H), 1.98-1.90 (m, E; Peak 1 N-{2-[(3S,4R)-3-fluoro-4- (methylamino) piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- amine or N-{2- [(3R,4S)-3- fluoro-4- (methylamino)piperidin-1-yl]

1H), 1.83-1.75 (m, 1H), 1.51 (d, J = 6.0 Hz, 3H), 1.38-1.34 (m, 6H).pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)isoquinolin-3- amine 308

574 1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.96 (s, 1H), 8.40 (s,1H), 7.99 (d, J = 5.6 Hz, 1H), 7.92 (s, 1H), 6.50 (d, J = 5.6 Hz, 1H),5.09 (d, J = 4.4 Hz, 1H), 4.77 (t, J = 8.0 Hz, 1H), 4.54-4.38 (m, 5H),4.35- 4.26 (m, 2H), 4.26-4.16 (m, 1H), 3.89 (t, J = 7.2 Hz, 1H),3.53-3.35 (m, 3H), 3.32-3.15 (m, 3H), 2.90 (s, 3H), 2.85-2.76 (m, 1H),1.41 (d, J = 6.0 Hz, 3H), 1.22 (t, J = 6.8 Hz, 6H). S; Peak 1(3R,4S,5S)-3- fluoro-1-[4- ({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph- thyridin-3- yl}amino)pyrimidin-2-yl]- 5-methoxy- piperidin-4-ol or (3S,4R,5R)-3- fluoro-1-[4-({8-[(2R,3S)-3- (methanesulfonyl-

methyl)-2- methylazetidin-1- yl]-5-(propan-2- yl)-2,7-naph- thyridin-3-yl}amino) pyrimidin-2-yl]- 5-methoxy- piperidin-4-ol 309

574 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.58 (s, 1H), 8.07 (d, J =5.6 Hz, 1H), 7.60 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 6.53 (d, J = 8.0Hz, 1H), 6.20 (d, J = 5.6 Hz, 1H), 4.79 (dt, J = 9.2, 12.9 Hz, 1H),4.84- 4.73 (m, 1H), 4.54-4.45 (m, 1H), 4.29-4.19 (m, 1H), 3.74-3.55 (m,3H), 3.50-3.41 (m, 1H), 3.40- 3.27 (m, 2H), 3.09-2.97 (m, 2H), 2.96 (s,3H), 2.60 (s, 3H), 2.14-2.02 AA; Peak 1 N-{2-[(4S)-3,3- difluoro-4-(methylamino) piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin-1- yl]-5-(propan-2-yl)isoquinolin-3- amine or N-{2- [(4R)-3,3- difluoro-4- (methylamino)piperidin-1-yl]

(m, 1H), 1.80-1.69 (m, 2H), 1.51 (d, J = 6.0 Hz, 3H), 1.40-1.32 (m, 6H).pyrimidin-4-yl}- 8-[(2R,3S)-3- (methanesulfonyl- methyl)-2-methylazetidin- 1-yl]-5-(propan- 2-yl)isoquinolin- 3-amine 310

574 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.58 (s, 1H), 8.07 (d, J =5.6 Hz, 1H), 7.57 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 6.53 (d, J = 8.0Hz, 1H), 6.20 (d, J = 5.6 Hz, 1H), 4.83-4.72 (m, 1H), 4.70- 4.64 (m,1H), 4.54-4.45 (m, 1H), 4.30-4.21 (m, 1H), 3.75-3.56 (m, 3H), 3.52-3.42(m, 1H), 3.41- 3.29 (m, 2H), 3.08-2.97 (m, 2H), 2.96 (s, 3H), 2.60 (s,3H), 2.12-2.04 (m, 1H), 1.78-1.69 (m, AA; Peak 1 N-{2-[(4R)-3,3-difluoro-4- (methylamino) piperidin-1-yl] pyrimidin-4-yl}- 8-[(2R,3S)-3-(methanesulfonyl- methyl)-2- methylazetidin- 1-yl]-5-(propan-2-yl)isoquinolin- 3-amine or N- {2-[(4S)- 3,3-difluoro- 4(methylamino)piperidin-1-yl]

2H), 1.51 (d, J = 6.0 Hz, 3H), 1.39-1.34 (m, 6H). pyrimidin-4-yl}-8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- amine 311

543 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.92 (s, 1H), 9.06 (s, 1H), 8.67(s, 1H), 8.00 (d, 1H, J = 5.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.57 (d,1H, J = 8.0 Hz), 6.46 (d, 1H, J = 5.7 Hz), 5.15 (d, 1H, J = 5.0 Hz),4.81-4.59 (m, 3H), 4.39 (d, 1H, J = 13.2 Hz), 4.19 (q, 1H, J = 6.2 Hz),3.97-3.79 (m, 1H), 3.57 (ddt, 5H, J = 27.5, 13.9, 7.3 Hz), 3.43-3.33 (m,1H), 3.00 (s, 3H), 2.89 (q, 1H, J = 7.2 Hz), 1.77-1.69 (m, 2H), 1.43 (d,3H, J = 6.0 Hz), 1.31 (dd, 6H, J = 6.7, 4.9 Hz). (3R,4S)-3- fluoro-1-[4-({8-[(2R,3S)-3- (methanesulfonyl- methyl)-2- methylazetidin-1-yl]-5-(propan-2- yl)isoquinolin-3- yl}amino) pyrimidin-2-yl]piperidin-4-ol 312

572 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.70 (s, 1H), 9.04 (d, 2H, J = 8.9Hz), 7.99 (d, 1H, J = 5.7 Hz), 7.60 (d, 1H, J = 8.2 Hz), 6.70 (d, 1H, J= 5.7 Hz), 6.51 (d, 1H, J = 8.2 Hz), 5.11-4.84 (m, 3H), 4.64 (t, 1H, J =7.5 Hz), 4.60-4.50 (m, 1H), 4.19 (t, 1H, J = 6.3 Hz), 3.73-3.41 (m, 5H),3.36 (s, 3H), 3.28- 3.14 (m, 1H), 3.00 (s, 4H), 2.89 (q, 1H, J = 7.2Hz), 2.01-1.95 (m, 2H), 1.86-1.76 (m, 2H), 1.63 (s, 6H), 1.42 (d, 3H, J= 6.0 Hz). No chiral sepa- ration 5-(2-amino- propan-2-yl)-N-(2-((3R,4S)- 3-fluoro-4- methoxy- piperidin-1-yl) pyrimidin-4-yl)-8-((2R,3S)-2- methyl-3- ((methylsulfonyl) methyl)azetidin-1-yl)isoquinolin- 3-amine 313

594 1H-NMR (400 MHz, 6d- DMSO) δ ppm 10.00 (s, 1H), 9.07 (s, 1H), 8.54(s, 1H), 8.03 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.62-6.53(m, 2H), 5.31 (d, 1H, J = 5.8 Hz), 4.84-4.78 (m, 1H), 4.66 (t, 1H, J =7.5 Hz), 4.53 (dd, QQ; Peak 2 (3S,4S)-5,5- difluoro-1-(4-((5-isopropyl-8- ((2R,3S)-2- methyl-3- ((methylsulfonyl)methyl)azetidin- 1-yl)isoquinolin- 3-yl)amino)

1H, J = 12.2, 4.4 Hz), 4.20 (p, 1H, J = 6.0 Hz), 3.85- 3.44 (m, 7H),3.25-3.12 (m, 1H), 3.00 (s, 3H), 2.89 (h, 1H, J = 7.3 Hz), 1.43 (d, 3H,J = 6.0 Hz), 1.30 (dd, 6H, J = 10.5, 6.7 Hz). pyrimidin-2-yl)- 4-(²H3)methoxy- piperidin-3-ol or (3R,4R)-5,5- difluoro-1-(4- ((5-isopropyl-8-((2R,3S)-2- methyl-3- ((methylsulfonyl) methyl)azetidin-1-yl)isoquinolin- 3-yl)amino) pyrimidin-2-yl)- 4-(²H3) methoxy-piperidin-3-ol 314

594 1H-NMR (400 MHz, 6d- DMSO) δ ppm 9.99 (s, 1H), 9.07 (s, 1H), 8.54(s, 1H), 8.03 (d, 1H, J = 5.7 Hz), 7.43 (d, 1H, J = 8.0 Hz), 6.62- 6.53(m, 2H), 5.30 (d, 1H, J = 5.8 Hz), 4.84-4.78 (m, 1H), 4.67 (t, 1H, J =7.5 Hz), 4.58-4.48 (m, 1H), 4.20 (t, QQ; Peak 1 (3S,4S)-5,5-difluoro-1-(4- ((5-isopropyl- 8-((2R,3S)-2- methyl-3- ((methylsulfonyl)methyl)azetidin- 1-yl)isoquinolin- 3-yl)amino)

1H, J = 6.2 Hz), 3.79-3.44 (m, 7H), 3.26-3.13 (m, 1H), 3.00 (s, 3H),2.89 (q, 1H, J = 7.3 Hz), 1.43 (d, 3H, J = 6.0 Hz), 1.30 (dd, 6H, J =6.7, 4.1 Hz). pyrimidin-2-yl)- 4-(²H3) methoxy- piperidin-3-ol or(3R,4R)-5,5- difluoro-1-(4- ((5-isopropyl-8- ((2R,3S)-2- methyl-3-((methylsulfonyl) methyl)azetidin- 1-yl)isoquinolin- 3-yl)amino)pyrimidin-2-yl)- 4-(²H3)methoxy- piperidin-3-ol 315

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.91 (s, 1H), 9.03 (s, 1H), 8.71(s, 1H), 7.98 (d, 1H, J = 5.7 Hz), 7.22 (d, 1H, J = 7.9 Hz), 6.45 (dd,2H, J = 8.5, 6.8 Hz), 4.86 (d, 1H, J = 50.9 Hz), 4.64 (t, 2H, J = 7.3Hz), 4.41 (d, 1H, J = 13.3 Hz), 4.17 (p, 1H, J = 6.1 Hz), 3.67-3.46 (m,5H), 3.33-3.27 (m, 1H), 2.97 (s, 3H), 2.85 (p, 1H, J = 7.3 Hz),2.13-2.07 (m, 1H), 1.79-1.56 (m, 2H), 1.39 (d, 3H, J = 6.0 Hz),1.00-0.91 (m, 2H), 0.67-0.58 (m, 2H). No Chiral Sepa- ration5-cyclopropyl- N-(2-((3S,4R)- 3-fluoro-4- (²H3)piperidin- 1-yl)pyrimidin-4-yl)- 8-((2R,3S)-2- methyl-3- ((methylsulfonyl)methyl)azetidin- 1-yl)isoquinolin- 3-amine 316

558 1H-NMR (300 MHz, 6d- DMSO) δ ppm 9.91 (s, 1H), 9.03 (s, 1H), 8.71(s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.22 (d, 1H, J = 7.8 Hz), 6.50- 6.39(m, 2H), 4.85 (d, 1H, J = 49.2 Hz), 4.64 (t, 2H, J = 7.4 Hz), 4.41 (d,1H, J = 13.2 Hz), 4.17 (t, 1H, J = 6.2 Hz), 3.69-3.46 (m, 5H), 3.32-3.26(m, 1H), 2.97 (s, 3H), 2.86 (q, 1H, J = 7.1 Hz), 2.22-1.99 (m, 1H),1.74-1.68 (m, 2H), 1.39 (d, 3H, J = 5.9 Hz), 0.95 (d, 2H, J = 8.4 Hz),0.61 (t, 2H, J = 5.2 Hz). No Chiral Sepa- ration 5-cyclopropyl-N-(2-((3R,4S)-3- fluoro-4-(²H3) piperidin-1-yl) pyrimidin-4-yl)-8-((2R,3S)-2- methyl-3- ((methylsulfonyl) methyl)azetidin-1-yl)isoquinolin- 3-amine

Biological Example 1. Biochemical EGFR Inhibition Assays

Inhibitory effects of the compounds of the disclosure were measured inbiochemical assays that measure the phosphorylation activity of EGFRenzyme phosphorylates 2.5 micromolar 5-FAM-EEPLYWSFPAKKK-CONH₂ peptidesubstrate (FL-Peptide 22, PerkinElmer, 760366) in the presence ofadenosine-5′-triphosphate (ATP) and varying concentrations of the testcompound in 100 mM 2-[4-(2-hydroxyethyl)piperazin-1-yl] ethanesulfonicacid (HEPES), pH 7.5, 10 mM MgCl₂, 0.015% Brij-35, 1 mM dithiothreitol(DTT), 1.0% dimethylsulfoxide (DMSO). Assays were performed at 1.0 mMATP or at ATP Km of the EGFR enzymes. Reactions proceeded until between10% to 20% total peptides were phosphorylated at room temperature (25°C.) and were terminated with 35 mM2,2′,2″,2′″-(ethane-1,2-diyldinitrilo)tetraacetic acid (EDTA). Productwas detected using the Caliper mobility shift detection method where thephosphorylated peptide (product) and substrate were electrophoreticallyseparated and measured. Percent activity was plotted against logconcentration of compound and points to generate an apparent IC₅₀. Thefollowing enzyme forms of EGFR were examples that were used in theseassays:

EGFR WT (SignalChem, E10-112G)

EGFR (L858R T790M C797S) (SignalChem, E10-122VG)

EGFR (d746-750) T790M C797S (SignalChem, E10-122UG)

EGFR L858R (SignalChem, E10-122BG)

EGFR (d746-750) (SignalChem, E10-122JG)

Biological Example 2. NCI-H1975 pEGFR AlphaLISA Assays

Inhibitory effects of the compounds of the disclosure were evaluated incellular assays that measure level of intracellular phosphorylation ofEGFR in NCI-H1975 cell line that harbors the EGFR L858R T790M mutations(ATCC, CRL-5908) using AlphaLISA sureFire ultra p-EGFR (Tyr1068) assaykit (PerkinElmer, ALSU-PEGFR-A50K). The NCI-H1975 cells were seeded at12.5K/well in 22 μL into 384 well opti plate (PerkinElmer, 6007299) andadhering overnight at 37 C/5% CO₂. On the next day, the test compoundsand DMSO control were added into H1975 cell plate followed by incubationat 37 C/5% CO₂ for 4-5 hours. The cells were then spin down in the384-well plate and lysed with 10 μL of 1×AlphaLISA lysis buffer followedby shaking at 600 rpm for 10 minutes at room temperature. After that, 5μL of an acceptor bead mix was added to each well followed by incubationat room temperature for 1.5-2 h in dark. Then 5 μL of a donor bead mixwas added to each well followed by overnight incubation at roomtemperature in dark. On the next day, the plate was read at a compatibleplate reader to obtain pEGFR signal. Percent of pEGFR inhibition wasplotted against log concentration of compounds to generate IC₅₀ values.

Biological assay data of the test compounds are provided in Table 2below. For inhibitory activity against EGFR LRTMCS mutant, the followingdesignations are used: ≤15 nM=A; 15.1-20 nM=B; 20.1-30 nM=C; and30.1-100 nM=D. For inhibition of phosphorylation of mutant EGFR incells: ≤10 nM=A; 10.1-20 nM=B; 20.1-30 nM=C; and 30.1-50 nM=D.

TABLE 2 Tabularized Data: Compound Ext Enz LRTMCS Ext pEGFR H1975 Number(nM) (nM) 1 B D 2 A D 3 C D 4 A D 5 A B 6 A C 7 A B 8 A D 9 A B 10 A D11 A D 12 A D 13 A D 14 B D 15 A D 16 C B 17 A B 18 A A 19 B B 20 B D 21C D 22 A A 23 A B 24 A C 25 A D 26 A A 27 A B 28 A A 29 A A 30 A A 31 AB 32 A C 33 A A 34 A B 35 A D 36 A A 37 A B 38 A A 39 A D 40 A A 41 A A42 A B 44 A A 45 A B 46 A A 47 B A 48 A A 49 A A 50 A A 51 A C 52 A A 53A A 54 A D 55 A A 56 A B 57 A B 58 B C 59 A B 60 A C 61 A D 62 A A 63 AA 64 A A 65 A A 66 A A 67 A A 70 A A 71 A A 72 A A 73 A A 74 A A 75 A A76 A A 77 B D 78 A C 79 A B 80 A D 81 A A 82 A A 83 A A 84 A B 85 A B 86C D 87 A C 88 A C 89 A A 90 A A 91 A A 92 A A 93 A A 94 A C 95 C B 96 CB 97 A A 98 A B 99 A B 100 A A 101 A B 102 A C 103 A B 104 A B 105 A A106 A A 107 A B 108 A A 109 A A 110 A A 111 A A 112 A B 113 A B 114 D D115 A A 116 A B 117 A A 118 A A 119 B C 120 B B 121 B A 122 A A 123 A A124 A A 126 A A 127 A A 128 A A 129 A A 130 A A 131 A A 132 A A 133 A A134 A A 135 A A 136 A B 137 A A 138 A A 139 A A 140 A A 141 A B 142 A C143 A A 144 A A 145 B C 146 B B 147 A B 148 A A 149 B B 150 A C 151 A A152 A A 153 A B 154 A C 155 A A 156 A A 157 A A 158 B B 159 B C 160 B D161 A A 162 A A 163 A D 164 B A 165 A C 166 D D 167 A B 168 A B 169 B D170 A A 171 A A 172 A C 173 B C 174 A B 175 A A 176 A A 177 A A 178 A A179 A A 180 A B 181 A B 182 A A 183 B A 184 A A 185 C A 186 A A 187 D B188 A A 189 A A 190 A A 191 A A 192 A B 193 A A 194 A A 195 A A 196 A B197 A D 198 B A 199 A B 200 B A 201 C A 202 C B 203 B A 204 A A 205 A A206 A A 207 A B 208 A B 209 A D 210 C B 211 C A 212 A A 213 A A 214 A A215 A A 216 A B 217 A C 218 A A 219 A A 220 A A 221 A D 222 A A 223 C D224 B A 225 A A 226 D D 227 C D 228 A A 229 A A 230 B A 231 A A 232 D A233 A A 234 C C 235 A A 236 A B 237 D C 238 A A 239 A A 240 A A 241 A B242 A A 243 A A 244 A A 245 A A 246 A A 247 A A 248 A A 249 A A 250 A A251 B A 252 C A 253 A A 254 A A 255 C A 256 C A 257 B B 258 A A 259 A A260 A A 261 A A 262 A A 263 B B 264 A A 265 A A 266 A A 267 A A 268 D C269 A A 270 A B 271 A A 272 A A 273 A C 274 B B 275 B D 276 A A 277 A B278 C C 279 D C 280 A A 281 A A 282 A A 283 A A 284 A A 285 A A 286 B B287 C B 288 A A 289 A A 290 A A 291 A A 292 A A 293 A A 294 C A 295 A A296 D B 297 A A 298 A A 299 A A 300 A A 301 A A 302 B A 303 B A 304 A A305 A A 306 C C 307 C B 308 A B 309 B A 310 A A 311 A A 312 A N/A 313 CA 314 D A 315 A A 316 A A

Biological Example 3. Biochemical EGFR Inhibition Assays

Inhibitory effects of the compounds of the disclosure were measured inbiochemical assays that measure the phosphorylation activity of EGFRenzyme phosphorylates 2.5 micromolar 5-FAM-EEPLYWSFPAKKK-CONH₂ peptidesubstrate (FL-Peptide 22, PerkinElmer, 760366) in the presence ofadenosine-5′-triphosphate (ATP) and varying concentrations of the testcompound. Kinase reaction was initiated by mixing of EGFR enzyme,fluorescent labeled substrate peptide, ATP, and the test compound in 100mM 2-[4-(2-hydroxyethyl)piperazin-1-yl] ethanesulfonic acid (HEPES), pH7.5, 10 mM MgCl₂, 0.015% Brij-35, 1 mM dithiothreitol (DTT), 1.0%dimethylsulfoxide (DMSO). Assays were performed at 1.0 mM ATP or at ATPKm of the EGFR enzymes. Reactions proceeded until between 10% to 20%total peptides were phosphorylated at room temperature (25° C.) and wereterminated with 35 mM 2,2′,2″,2′″-(ethane-1,2-diyldinitrilo)tetraaceticacid (EDTA). EGFR enzymatic activity was monitored using the PerkinElmer electrophoretic mobility shift technology platform (the Calipermobility shift detection method) where the phosphorylated peptide(product) and substrate were electrophoretically separated and measured.Percent activity was plotted against log concentration of compound andpoints to generate an apparent IC₅₀. The following enzyme forms of EGFRwere examples that were used in these assays:

EGFR WT (SignalChem, E10-112G)

EGFR (L858R T790M C797S) (SignalChem, E10-122VG)

EGFR (d746-750) T790M C797S (SignalChem, E10-122UG)

EGFR L858R (SignalChem, E10-122BG)

EGFR (d746-750) (SignalChem, E10-122JG)

EGFR (D770_N771insNPG T790M) (SignalChem, E10-132TG)

EGFR (D770_N771insNPG) (SignalChem, E10-132GG)

Biological assay data of the test compounds are provided in the tablebelow. For inhibitory activity against EGFR_D770_N771insNPG/T790Mmutant, the following designations are used: ≤20 nM=A; 20.1-100 nm=B;100.1 nM-250 nM=C; and 250.1-750 nM=D.

TABLE 3 Compound Number Enz EGFR_D770_N771insNPG/T790M 2 D 7 D 128 B 265C

Biological Example 4. pEGFR_LR/TM/G796S AlphaLISA Assay

Mutant EGFR expressing Ba/F3 cells were resuspended in fresh 10% FBSRPMI and plated at 1.0×10⁶ cells/mL. On the next day, the cells wereharvested and diluted in fresh medium at 1.25×10⁶ cells/mL. 40 μL ofcells were added to each well of a 384-well microplate (Corning 3764).In a clear 384-well polypropylene microplate, test compounds and DMSOwere added. DMSO was a negative control and staurosporine was a positivecontrol. The cell plate was placed in a humidified 37° C. incubator for4 hrs. The cell plate was spun to pellet the cells and the media wasremoved. 10 μL of 1×AlphaLISA Lysis Buffer with 1× protease andphosphatase inhibitors was added to the cells and plate was shaken at600 rpm for 30 min. The cell lysates were transferred from cell plate toa white opaque 384-well microplate (OptiPlate-384). 5 μL of acceptor mixwas added to the cell lysate and the plate was shaken at 600 rpm for 10min, gently tapped and sealed with foil. It was then incubated at RT for1.5-2 hr. Under low light conditions, lx donor mix was prepared rightprior to use. 5 μL of donor mix was added to the plate under subduedlighting or green filters. The plate was shaken at 600 rpm for 10 min,gently tapped and sealed with foil. It was then incubated overnight atRT in dark. After overnight incubation, the plate was read on anEnVision Multilabel Reader. All IC₅₀ representative curves were plottedusing GraphPad Prism (version 8.00 for Windows, GraphPad Software, SanDiego Calif. USA). The percentage of inhibition on EGFR phosphorylationwas calculated following equation below:

${\%{Inhibition}} = {100 \times \frac{{pEGFR_{HC}} - {pEGFR_{cpds}}}{{pEGFR_{HC}} - {pEGFR_{LC}}}}$

An IC₅₀ was calculated by fitting the curve using Nonliner fit withlog(inhibitor) vs. response−Variable slope (four parameters) model.

Biological assay data of the test compounds are provided in Table 4below. For inhibitory activity against pEGFR_LR/TM/G796S mutant, thefollowing designations are used: ≤20 nM=A; 20.1-100 nm=B; 100.1 nM-250nM=C; and 250.1-750 nM=D.

TABLE 4 Ext pEGFR_LR/TM/G796S Compound Number GMean IC₅₀ (nM) 55 A 111 B117 D 118 D 282 B 283 B

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Z is O or NH;each A¹, A², and A³ is independently N or CR; wherein each R isindependently H, halogen, or CH₃; Ring A is 4-12 membered heterocyclyl;each R¹ is independently halogen, CN, OH, NR_(a)R_(b), C₁-C₄ alkyl,C₁-C₄ alkoxy, C₃-C₆ cycloalkyl or —O—C₃-C₆ cycloalkyl, wherein thealkyl, alkoxy or cycloalkyl represented by R¹ or in the grouprepresented by R¹ is optionally substituted with 1 to 3 groups selectedfrom deuterium, halogen, OH, NR_(a)R_(b), C₁-C₂ alkyl, and C₁-C₂ alkoxy;and/or m is 0, 1, 2, 3, 4, 5, or 6; R² is H, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, or C₃-C₆ cycloalkyl, wherein the alkyl, alkoxy or cycloalkylrepresented by R² is optionally substituted with 1 to 3 groups selectedfrom halogen and OH; R³ is H or methyl; R⁴ is H or methyl; R⁵ is H,C₁-C₄ alkyl, C₃-C₆ cycloalkyl or 4-6 membered monocyclic heterocyclyl,wherein the alkyl, cycloalkyl or heterocyclyl represented by R⁵ isoptionally substituted with 1 to 3 three groups selected from halogen,CN, OH, NR_(a)R_(b), C₁-C₂ alkyl, and C₁-C₂ alkoxy; R⁶ is H or C₁-C₄alkyl optionally substituted with 1 to 3 three groups selected fromhalogen, CN, OH, NR_(a)R_(b), and C₁-C₂ alkoxy; and each R_(a) and R_(b)is independently H or C₁-C₄ alkyl.
 2. The compound of claim 1, whereinthe compound is represented by structural formula (II-A), (II-B),(II-C), (II-D), or (II-E):

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, wherein the compound is represented by structural formula (II-A):

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim3, or a pharmaceutically acceptable salt thereof, wherein Z is O.
 5. Thecompound of claim 4, or a pharmaceutically acceptable salt thereof,wherein R² is H, fluorine, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₃-C₆cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl represented by R²is optionally substituted with 1 to 3 groups selected from halogen andOH.
 6. The compound of claim 5, or a pharmaceutically acceptable saltthereof, wherein R⁶ is H, methyl, ethyl, C₁-C₂ haloalkyl, or C₁-C₂aminoalkyl.
 7. The compound of claim 6, or a pharmaceutically acceptablesalt thereof, wherein R⁵ is H; C₁-C₄ alkyl optionally substituted with 1to 3 three groups selected from halogen, CN, and NR_(a)R_(b); C₃-C₆cycloalkyl; or 4-6 membered monocyclic heterocyclyl optionallysubstituted with C₁-C₄ alkyl; and wherein R_(a) and R_(b) are eachindependently selected from H, methyl and ethyl.
 8. The compound ofclaim 7, or a pharmaceutically acceptable salt thereof, wherein Ring Ais 4-7 membered monocyclic heterocyclyl optionally substituted with 1-6R¹.
 9. The compound of claim 7, or a pharmaceutically acceptable saltthereof, wherein Ring A is 7-12 membered bicyclic heterocyclyloptionally substituted with 1-6 R¹.
 10. The compound of claim 8, or apharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, 4, or 5;and each R¹ is independently halogen, CN, OH, NR_(a)R_(b), C₁-C₄ alkyl,C₁-C₄ alkoxy, —O—C₃-C₆ cycloalkyl, wherein the alkyl, alkoxy, orcycloalkyl represented by R¹ or in the group represented by R¹ isoptionally substituted with 1 to 3 groups selected from deuterium,halogen, OH, NR_(a)R_(b), C₁-C₂ alkyl, and C₁-C₂ alkoxy.
 11. Thecompound of claim 3, or a pharmaceutically acceptable salt thereof,wherein R² is H, F, methyl, ethyl, isopropyl, CH(CH₃)CH₂F, CH(CH₃)CH₂OH,CF₃, OCH₃, OCH₂CH₃, or cyclopropyl.
 12. The compound of claim 11, or apharmaceutically acceptable salt thereof, wherein R⁶ is H, CH₃, orCH₂NH₂.
 13. The compound of claim 12, or a pharmaceutically acceptablesalt thereof, wherein Ring A is optionally substituted with 1-6 R¹, andRing A is pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl,2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.1]octanyl,6-oxa-2-azabicyclo[3.2.1]octanyl, 6-oxa-3-azabicyclo[3.2.1]octanyl,8-oxa-3-azabicyclo[3.2.1]octanyl, hexahydro-1H-furo[3,4-b]pyrrolyl,hexahydro-1H-furo[3,4-c]pyrrolyl, 1-oxa-7-azaspiro[3.5]nonan-7-yl,1,4-dioxa-8-azaspiro[4.5]decan-8-yl or1,4-dioxa-9-azaspiro[5.5]undecan-9-yl.
 14. The compound of claim 13, ora pharmaceutically acceptable salt thereof, wherein at least one R¹ isOH, C₁-C₄ alkoxy, or —O—C₃-C₆ cycloalkyl, wherein the alkoxy orcycloalkyl represented by R¹ or in the group represented by R¹ isoptionally substituted with 1 to 3 groups selected from deuterium,halogen, OH, NR_(a)R_(b), C₁-C₂ alkyl, and C₁-C₂ alkoxy.
 15. Thecompound of claim 3, or a pharmaceutically acceptable salt thereof,wherein each R¹ is independently F, CN, OH, NH₂, CH₃, CH₂CH₃, CHF₂,CH(OH)CH₃, CH₂OH, CH₂NH₂, CH₂CH₂NH₂, OCH₃, OCD₃, OCH₂CH₂OH,OCH₂CH(OH)CH₃, OCH₂C(OH)(CH₃)₂, OCH₂CH₂OCH₃, OCH₂CH₂NH₂, OCH₂CH₂NHCH₃,OCH₂CH₂N(CH₃)₂, —O-cyclopropyl, NHCH₃, or N(CH₃)₂.
 16. The compound ofclaim 15, or a pharmaceutically acceptable salt thereof, wherein


17. The compound of claim 16, or a pharmaceutically acceptable saltthereof, wherein R² is H or isopropyl.
 18. The compound of claim 17, ora pharmaceutically acceptable salt thereof, wherein Ring A ispiperidinyl optionally substituted with 1-6 R¹.
 19. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and claim1, or a pharmaceutically acceptable salt thereof.
 20. A method oftreating a cancer, comprising administering a subject in need thereof aneffective amount of claim 1, or a pharmaceutically acceptable saltthereof. 21-25. (canceled)
 26. A method of inhibiting epidermal growthfactor receptor (EGFR), comprising administering to a subject in needthereof an effective amount of claim 1, or a pharmaceutically acceptablesalt thereof.